Symposium: Nutrition, Immunomodulation
and AIDS
CARL GRÃœNFELD3 AND KENNETH R. FEINGOLD Department of Medicine, University of California, San Francisco, CA and Metabolism Section Department of Veterans Affairs Medical Center, San Francisco, CA 94121 (7). A single factor (named cachectin) that might me diate both hypertriglyceridemia and wasting was ten tatively identified as tumor necrosis factor (TNF). An initial report that TNF levels were elevated in AIDS patients (8) led to the conclusion that TNF was the cause of cachexia in AIDS. However, as will be outlined below, the metabolic disturbances that occur during infection are more complex than originally hypothesized and are not due to a single cytokine. Further, the hypertriglyceridemia of infection is not mechanistically linked to cachexia; instead, hypertriglyceridemia may play a role in host defense.
ABSTRACT The hypertriglyceridemia of infection is mediated by many of the cytokines that regulate the immune response, including the tumor necrosis factors, the interleukins and the interferons. In the acquired immunodeficiency syndrome (AIDS),4 hypertriglycer idemia is most likely due to increased circulating levels of interferon alpha. Both in AIDS and in animal models there is no direct association between the presence of hypertriglyceridemia and the syndrome of wasting. Rather, circulating lipoproteins may neutralize infec tious organisms and therefore contribute to host defense. J. Nutr. 122: 749-753, 1992. INDEXING KEY WORDS:
•acquired immunodeficiency syndrome •cytokines •lipids •cachexia •infection
TNF AND LIPID METABOLISM IN VIVO Administration of TNF to rats induces a rapid in crease in plasma TG due to VLDL of normal compo-
Hypertriglyceridemia commonly occurs during in fection (1). Early studies indicated three mechanisms by which infection might increase triglycérides(TG)4: 1} Increased hepatic de novo synthesis of fatty acids (FA)leading to increased secretion of very low density lipoprotein (VLDL) (2). 2) Increased adipose tissue lipolysis with the mobilized FA being reesterified into TG in the liver and then resecreted as VLDL rather than being oxidized (3). 3) Decreased levels of lipo protein Upase (LPL)leading to decreased clearance of TG-rich lipoproteins (4, 5). These changes are thought to be mediated by cytokines secreted by the host in response to infection (6). It is also thought that the cachexia associated with infection is due to cytokines. Because hypertriglyc eridemia and cachexia may occur simultaneously dur ing infection (5), it was originally proposed that a sin gle factor caused both cachexia and hypertriglyceride mia by decreasing the storage of fat in adipose tissue
1Presented as part of a symposium: Nutrition, Immunomodulation and AIDS, given at the 75th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlanta, GA, April 25, 1991. The symposium was sponsored by the American Institute of Nutrition and supported in part by grants from Campbell Institute for Research and Technology, Clintgec International Inc., BristolMyers Company and Mead Johnson Research Center. Guest editor for this symposium was R. R. Watson, Department of Family and Community Medicine, University of Arizona, Tucson, AZ. 2This work was supported by grants from the Department of Veterans Affairs, the Universitywide AIDS Research Program of the University of California and the National Institutes of Health (DK-40990|. Dr. Grunfeld is a recipient of a Clinical Investigator Award from the Department of Veterans Affairs. 3To whom correspondence should be addressed: Metabolism Section (11IF), VA Medical Center, 4150 Clement Street, San Fran cisco, CA 94121. 4Abbreviations: TG, triglycéride; LPS,endotoxin,-AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; VLDL, very low density lipoprotein; HDL, high density lipoprotein; LDL, low density lipoprotein; LPL lipoprotein lipase; FA, fatty acid.
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The Role of the Cytokines, Interferon Alpha and Tumor Necrosis Factor in the Hypertriglyceridemia and Wasting of AIDS12
750
GRUNFELD
OTHER
CYTOKINES INFLUENCE METABOLISM IN VIVO
LIPID
In mice, TNF, interleukin (IL)-l, IL-6 and interferon (IFN) alpha all increase hepatic FA synthesis within 30 min of administration, with the increase for most
cytokines being sustained for many hours (6). It is of interest that the doses for stimulation of hepatic FA synthesis by TNF and IL-1 are similar to the doses that produce fever (endogenous pyrogen activity). There fore, cytokine-stimulated hepatic lipogenesis should occur under physiological conditions of infection that produce TNF or IL-1 (6). Studies on the mechanism of the stimulation of he patic FA synthesis suggested that there are two classes of lipogenic cytokines. TNF, IL-1 and IL-6 stimulate hepatic FA synthesis by increasing hepatic levels of citrate, the major allosteric activator of acetyl CoA carboxylase, the rate-limiting enzyme for FA synthesis (11). In contrast, IFN alpha works by a different and as yet unknown mechanism (11). Administration of IFN alpha with either TNF or IL-1 in low doses pro duces synergy whereas high doses lead to additivity in stimulating hepatic lipogenesis. On the other hand, there is no synergy or additivity when two cytokines from the same class (TNF and IL-1) are given simul taneously. IL-4 is a cytokine that shows inhibitory properties during the immune response. IL-4 administered alone has no effect on hepatic FA synthesis, but IL-4 inhibits the ability of TNF, IL-1 and IL-6 to stimulate hepatic lipogenesis (12). IL-4 counteracts the ability of cyto kines to increase hepatic citrate levels. As a conse quence, IL-4 is unable to block IFN-alpha-stimulated hepatic lipogenesis, confirming the two classes of li pogenic cytokines.
ARE CYTOKINE INDUCED CHANGES LIPID METABOLISM THE CAUSE OF CACHEXIA?
IN
It was originally proposed that cachectin (TNF) in duced both cachexia and hypertriglyceridemia through its effects on the fat cell; by decreasing LPL,TNF might decrease TG clearance and inhibit the storage of fat in adipose cells (7). Thus, the induction of hypertri glyceridemia and cachexia were proposed to be mech anistically linked. A large body of experimental data raised questions about this hypothesis. 1)If the ability to induce a catabolic state in cultured fat cells is the criterion for being cachectin, then IL-1 and the IFNs (which decrease the storage and promote the break down of TG in cultured fat cells in a manner similar to TNF) could equally be classified as cachectins (6). 2)TNF does not appear to have similar catabolic effects in cultured fat cells from rats or humans (6). 3) The catabolic effects that TNF induces in cultured fat cells do not occur in vivo. TNF does not increase plasma TG in rats by decreasing TG clearance and storage; rather, TNF increases hepatic lipogenesis and VLDL production. Additionally, there is no effect of TNF on adipose tissue FA synthesis in vivo (6).
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sition; plasma chylomicron levels were not increased in fed rats (6). Plasma TG remain elevated for 17 h as the VLDL is processed to TG-rich low density lipoprotein (LDL).Plasma TG are also increased in humans given TNF (9). Initial studies with crude cachectin (7) and, subse quently, recombinant TNF (6) showed that TNF re duced LPLactivity in cultured 3T3-L1 mouse fat cells. Therefore, TNF could potentially increase plasma TG by decreasing LPL, causing decreased clearance (stor age) of TG-rich lipoproteins. Although TNF does de crease LPL in epididymal fat pads of mice, rats and guinea pigs, this decrease requires several hours, sim ilar to the time course of TNF in 3T3-L1 cells (6). However, plasma TG rise within 45 min of adminis tration of TNF. More important, TNF does not sig nificantly decrease LPL activity in multiple other adi pose tissue sites or in muscle, and TNF increases total plasma postheparin lipase. As a consequence, TNF has no effect on the clearance of VLDL or chylomicron TG. These data raise questions as to whether cultured 3T3-L1 cells are a valid model for the effects of cytokines in vivo. Rather, TNF produces hypertriglyceridemia by rapidly increasing the VLDL production rate (6). TNF increases hepatic de novo FA synthesis and total he patic TG synthesis with newly synthesized TG ap pearing in plasma. TNF also rapidly (within 90 min) mobilizes FA from the periphery (10), which again is different from TNF-stimulated lipolysis in cultured fat cells, which requires several hours. During fasting, exercise or stress, mobilized FA are oxidized by the liver, but during infection they may be incorporated into hepatic TG and secreted as VLDL (3). TNF can induce similar reesterification of peripherally derived FA. When TNF-induced lipolysis is inhibited in vivo by the antilipolytic drug phenylisopropyladenosine, there is significant blunting of the TNF-induced in crease in serum TG (10). Thus, in chow-fed animals, the increase in hepatic VLDL production and plasma TG induced by TNF is due to a combination of in creased de novo hepatic FA synthesis and increased reesterification of peripherally derived FA. However, dietary conditions can influence the source of FA for TG synthesis. In sucrose-fed rats, where the basal rates of hepatic FA synthesis are markedly increased, TNF does not stimulate lipolysis and the TNF-induced in crease in the hepatic FA synthetic rate provides ade quate FA for induction of hypertriglyceridemia.
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that the hypertriglyceridemia of infection is not in evitably or mechanistically linked to the induction of cachexia as was originally proposed in the cachectin hypothesis. Human disease may have both hypertri glyceridemia and cachexia, but there is no evidence that the two are mechanistically linked (see below).
LIPIDS AND LIPOPROTEINS
IN AIDS
Serum TG levels in subjects with AIDS average twice that of controls (30, 31). Serum TG in subjects with HIV infection fall in between control and AIDS patients depending upon where the subjects are in the time course between asymptomatic HIV infection and development of AIDS. In contrast, serum cholesterol levels are decreased equally in both AIDS and HIVpositive subjects (unpublished data). Decreases are seen in high density lipoprotein (HDL) and LDL cho lesterol, apo B-100 (primarily found in LDL) and apo A-l (primarily found in HDL). When lipoprotein composition was analyzed, there was an increase in VLDL of normal composition in AIDS, whereas LDL and HDL were slightly TG-rich (unpublished data). As a consequence, the increase in plasma TG was almost entirely due to the increase in VLDL.
LACK OF CORRELATION BETWEEN HYPERTRIGLYCERIDEMIA AND WASTING IN AIDS Serum lipids were studied in subjects whose body composition had been studied (30). Half of the subjects with AIDS and HIV infection had hypertriglyceride mia and half showed wasting as determined by mea surement of total body potassium (30). However, there was no relationship between levels of serum TG and wasting in these subjects with AIDS and HIV infec tion. Patients with wasting had similar TG levels and prevalence of hypertriglyceridemia as those without wasting. Many patients were sequentially followed with time. Most of the patients with persistent hypertri glyceridemia showed prolonged periods of stable weight and lean body cell mass over several months (30). Thus, as seen in animal models, hypertriglycer idemia in human infection is not inevitably linked to the wasting syndrome.
CIRCULATING CYTOKINE LEVELS IN AIDS Multiple studies have found increased circulating IFN alpha levels in subjects with AIDS (see réf. 31 for
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Lastly and most important, TNF does not induce cachexia in the same way that was seen with crude cachectin [supernatants from endotoxin (LPS)-stimulated macrophages]. Daily injections of the same dose of crude cachectin produced persistent weight loss (13). In contrast, daily injection of the same dose of purified recombinant TNF leads to acute weight loss due to anorexia and negative fluid balance, but mul tiple laboratories have found that, with repeated in jections of the same dose of TNF, animals rapidly re cover from anorexia and gain weight back to the level of control animals (14-23). Because of the disappointing failure of TNF to mimic crude cachectin in inducing the syndrome of cachexia, other models had been developed in which TNF administration is associated with chronic weight loss. First, sequential escalation of TNF doses to levels that would initially be lethal can produce chronic weight loss in rodents, but this weight loss is also mostly due to anorexia and is similar to pair-fed ani mals (16). Other models for TNF induced anorexia/ cachexia are likely to require synergistic interactions between cytokines, such as we have found for lipogenesis. For example, catheterized rats show persistent anorexia and weight loss when chronically infused with TNF (24). However, chronically catheterized rats do not grow at normal rates, suggesting that inflam matory products generated at the catheterization site are already having physiological effects; these products could interact with TNF to produce weight loss. In addition, weight loss during continuous TNF infusion is also similar to that of pair-fed rats (24). Finally, a tumor genetically engineered to produce TNF causes weight loss when implanted into animals (25), but the interactions of TNF with other tumor products or with substances produced by host cells that have infiltrated the tumor have not been explored. Tumor-bearing an imals are known to be more susceptible to the toxic effects of TNF (26). In summary, administration of pure TNF alone does not reproduce the original syn drome of wasting that was found with crude cachectin, but TNF may contribute to cachexia when produced in conjunction with other mediators of the immune or inflammatory response, just as synergy is seen be tween TNF and IFN alpha in stimulating lipogenesis. Unlike the tachyphyllaxis to TNF, injection of IL-1 produces sustained anorexia and weight loss (27, 28). Treatment of cancer patients with IFN may also produce anorexia. Other as yet to be identified cyto kines may play important roles in the induction of cachexia, especially in promoting muscle protein deg radation (29). Although animals develop resistance to the anorectic effects of TNF during repeated administration, this is not a general resistance to all of TNF's activities. Chronic TNF administration leads to persistent ele vations in plasma TG in animals that have resumed eating and regained their weight (21).These data imply
AND AIDS
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GRUNFELD
IFN ALPHA DRIVES HYPERTRIGLYCERIDEMIA IN AIDS Given the difficulty in detecting elevations of serum TNF in AIDS it is not surprising that there is no cor relation between plasma TG and serum TNF levels (31). On the other hand, serum TG levels are correlated at a highly significant level (r = 0.446, P < 0.002) with IFN alpha levels. When patients were followed se quentially with time, their TG levels paralleled their IFN alpha levels. The mechanisms by which IFN alpha affects TGs in AIDS have recently been studied. LPL is decreased in subjects with AIDS and HIV infection (unpublished data). As a consequence, the clearance of TG from plasma is significantly slowed. In addition, there is a striking correlation (r = 0.783, P < 0.001) between serum IFN alpha levels and the change in TG clearance ip AIDS. Therefore, even under conditions where a cytokine might slow the clearance (hence storage) of TG, there is no direct link between those disturbances in lipid metabolism and wasting. Preliminary unpublished data also indicate that de novo hepatic FA synthesis is increased in subjects with HIV infection. A significant correlation was also found between basal rates of FA synthesis and circulating IFN alpha levels.
WHY DO DISTURBANCES IN LIPID METABOLISM OCCUR DURING INFECTION? The data presented above indicate that there is no direct association between disturbances of lipid or lipoprotein metabolism and wasting during infection. Yet these disturbances in lipid metabolism commonly occur in multiple types of infections (see réf.6 for review). The data presented above indicate that dis turbances in lipid metabolism are tightly linked to cytokines and the immunological response; multiple cytokines at low doses modulate the effect of lipid me tabolism through multiple receptors at multiple sites and by multiple mechanisms. The question must therefore be raised as to whether disturbances in lipid
metabolism could be beneficial to the host as part of the hepatic acute phase response. There are multiple lines of evidence that plasma lipoproteins can decrease the toxicity of microorgan isms. VLDL, LDL and HDL can bind LPSand decrease or prevent the ability of LPSto induce fever, hypoten sion and death in mice and rats (35, 36). In these stud ies lipoproteins and LPS were preincubated in vitro with lipoprotein-depleted plasma present. Although the ability of lipoproteins to detoxify LPS in vivo has not yet been demonstrated, there is evidence that VLDL from normal subjects contains bound and se questered LPS (36). Lipoproteins have also been shown to bind and/or neutralize multiple viruses, including mouse retroviruses (37), Epstein-Barr virus (38), Japanese encepha litis virus (39), rabies virus and vesicular stomatitis virus (40). Increased production of VLDL is a prominent dis turbance in lipid metabolism that occurs during in fection. There is no direct linkage between hypertriglyceridemia during infection and the wasting syn drome. However, lipoproteins may inactivate infectious agents. The body's ability to increase TG production represents a part of the acute phase re sponse that serves to maintain levels of protective li poproteins during infection.
LITERATURE CITED 1. Beisel, W. R. (1975) Metabolic response to infection. Annu. Rev. Med. 26: 9-20. 2. Guckian, J. D. (1973) Role of metabolism in pathogenesis of bacteremia due to Diplococcus pneumoniae in rabbits. J. Infect. Dis. 127: 1-8. 3. Wolfe, R. R., Shaw, J. H. F. & Durkot, M. J. (1985) Effect of sepsis on VLDL kinetics: Responses in basal state and during glucose infusion. Am. J. Physiol. 248: E732-E740. 4. Kaufmann, R. L., Maison, C. F. &. Beisel, W. R. (1976) Hypertriglyceridemia produced by endotoxin: Role of impaired trilyceride disposal mechanisms. J. Infect. Dis. 133: 548-555. 5. Rouzer, C. A. & Cerami, A. (1980) Hypertriglyceridemia as sociated with Trypanosoma bruceii bruceii infection in rabbits: Relative effect of triglycérideremoval. Mol. Biochem. Parasitol. 2:31-38. 6. Grunfeld, C. &. Feingold, K. R. (1991) The metabolic effects of tumor necrosis factor. Biotherapy 3: 143-148. 7. Beutler, B. & Cerami, A. (1986) Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 320: 584-588. 8. Lahdevirta, K., Maury, C. P. J., Teppo, A. M. & Repo, H. (1988) Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am. J. Med. 85:289-291. 9. Starnes, F., Jr., Warren, R. S., Jeevanandam, M.; Gabrilove, J. L, Larchian, W., Oettgen, H. F. & Brenman, M. E. (1988) Tumor necrosis factor and the acute metabolic response to in jury. J. Clin. Invest. 82: 1321-1325. 10. Feingold, K. R., Adi, S., Staprans, I., Moser, A. H., Neese, R., Verdier, J. A., Doerrler, W. & Grunfeld, C. (1990) Diet affects the mechanism by which TNF stimulates hepatic triglycéride production. Am. J. Physiol. 259: E177-E184.
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review). In fact, IFN alpha appears at about the time of the transition from asymptomatic HIV infection to AIDS. Although an initial study reported increased levels of TNF in AIDS (8), no significant differences in TNF levels had been found between AIDS and controls in six other cohorts of patients (31-34, unpublished data). Many AIDS patients in the first report (8)were studied during acute opportunistic infections, which may ac count for the ability to detect TNF in serum.
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14. Patton, J. S., Peters, P. M., McCabe, J., Grase, D., Hansen, S., & Chen, A. B. (1987) Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor ne crosis factor alpha in rodents. J. Clin. Invest. 80: 1587-1596. 15. Moldawer, L. L., Suaniger, G., Gelin, G. &. Lundholm, K. G. (1987) Interleukin-1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am. J. Physiol. 253: C766C773. 16. Tracey, K. G., Wei, H., Manogue, K. R., Fary, Y., Hesse, D. G., Nguyen, H. T., Juo, G. C., Beutler, B., Cotran, R. S., Cerami, A. & Lowry, S. F. (1988) Cachectin/tumor necrosis factor in duces cachexia, anemia and inflammation. J. Exp. Med. 167: 1211-1227. 17. Kettelhut, I. C. & Goldberg, A. L. (1988) Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue. J. Clin. Invest. 81: 13841389. 18. Socher,S. H., Friedman, A. & Martinez, D. (1988) Recombinant human-tumor necrosis factor induces acute reductions in foodintake and body-weight in mice. J. Exp. Med. 167: 1957-1962. 19. Stovroff, M. C., Fraker, D. L., Swedenborg, J. A. & Norton, J. A. (1988) Cachectin/tumor necrosis factor; a possible me diator of cancer anorexia in the rat. Cancer Res. 48: 4567-4572. 20. Kramer, S. M., Aggarwal, B. B., Essalu, T. E., McCabe, T. E., Ferraiolo, B. C., Figari, I. S. & Palladino, M. A., Jr. (1988) Characterization of the in vitro and in vivo species preference of human murine tumor necrosis factor alpha. Cancer Res. 48: 920-925. 21. Grunfeld, C., Wilking, H., Neese, R., Gavin, L. A., Moser, A. H., Culli, R., Serio, M. K. & Feingold, K. F. (1989) Per sistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/ cachectic effects in rats. Cancer Res. 49: 2554-2560. 22. Mahoney, S. M. &. Tisdale, M. J. (1989) Reversal of weight loss induced by tumor necrosis factor. Cancer Lett. 45: 167172. 23. Mullen, B. J., Harris, R. B. S., Patton, J. S. & Martin, R. J. (1990) Recombinant tumor necrosis factor alpha chronically administered in rats: Lack of cachectic effects. Proc. Soc. Exp. Biol. Med. 193: 318-325. 24. Michie, H. R., Sherman, M. L., Spriggs, D. R., Rounds, J., Chris tie, M. & Wilmore, D.W. (1989) Chronic TNF infusion causes anorexia but not accelerated nitrogen loss. Ann. Surg. 209: 1924.
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25. Oliff, A., Defeo-Jones, D., Boyer, M., Martinez, D., Kiefer, D., Vuocolo, G., Wolfe, A. & Sector, S. H. (1987) Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50: 555563. 26. Bartholeyns, J., Freudenberg, M. & Galanos, C. (1987) Growing tumors induce hypersensitivity to endotoxin and tumor necrosis factor. Infect. Immun. 55: 2230-2233. 27. Fujii, T., Sato, K., Ozawa, M., Kasano, K., Imamura, H., Kanaji, Y., Tsushima, T. & Shizume, K. (1989) Effect of interleukin-1 (IL-1) on tyroid hormone metabolism in mice: Stimulation by IL-1 of iodothyronine S'-deiodinating activity (Type I) in the liver. Endocrinology 124: 167-174. 28. Hellerstein, M. K., Meydani, S. N., Meydani, M., Wu, K. & Dinarello, C. A. (1989) Interleukin-1 induced anorexia in the rat. J. Clin. Invest. 84: 228-235. 2?. Goldberg, A. L., Kettelhut, I. C., Fonano, K., Egan, J. M. a Baracos, V. (1988) Activation of protein breakdown and prostaglandin E2production in rat skeletal muscle in fever is signaled by a macrophage product distinct from interleukin-1 or known cytokines. J. Clin. Invest. 81: 1378-1383. 30. Grunfeld, C., Kotler, D. P., Hamadeh, R., Tierney, A., Wang, J., Pierson, M. A., Jr. (1989) Hypertriglyceridemia in the ac quired immunodeficiency syndrome. Am. J. Med. 86: 27-31. 31. Grunfeld, C., Kotler, D. P., Shigenaga, J. K., Doerrler, W., Tier ney, A., Wang, J., Pierson, R. N. & Feingold, K. R. (1991) Circulating interferon alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am. J. Med. 90: 154162. 32. Reddy, M. M., Sorrell, S. J., Lange, M. & Grieco, M. H. (1988) Tumor necrosis factor and HIV P24 antigen serum of HIV-infected population. J. AIDS 1: 436-440. 33. Hommes, M., Romijin, J. A., Godfried, M. H., Eeftinck Schattenkerk, J. K. M., Burrman, W. A., Enden, E. & Sauerwein, H. P. (1990) Increased resting energy expenditure in human immunodeficiency virus-infected men. Metabolism 39: 11861190. 34. Dworkin, B., Seaton, T. &Wormsef, A. (1990) Tumor necrosis factor (TNF), metabolic rate, body composition and weight loss in HIV infected patients. Clin. Res. 38: 361A(abs.). 35. Ulevitch, R. J., Johnston, A. R. & Weinstein, D. B. (1979) New function for high density lipoproteins. Their participation in intravascular reactions of bacterial lipopolysaccharides. J. Clin. Invest. 64: 1516-1524. 36. Harris, H. W., Grunfeld, C., Feingold, K. R. & Rapp, J. H. (1990) Human VLDL and chylomicrons can protect against endotoxin-induced death in mice. J. Clin. Invest. 86: 696-792. 37. Sernatinger, J., Hoffman, A., Harman, D., Kane, J. P. & Levy, J. A. (1988) Neutralization of mouse xenotropic virus by li poproteins involves binding to the virions. J. Gen. Virol. 69: 2651-2661. 38. Chisari, F. V., Curtiss, L. K. & Jensen, F. C. (1981) Physiologic concentrations of normal human plasma lipoproteins inhibit the immortalization of peripheral B lymphocytes by the EpsteinBarr virus. J. Clin. Invest. 68: 329-336. 3».Shortridge, K. F., Ho, W. K., Oya, A. & Kobayashi, M. (1975) Studies on the inhibitory activities of human serum lipoproteins for Japanese encephalitis virus. Southeast Asian J. Trop. Med. Public Health 6: 461-466. 40. Seganti, L., Grassi, M., Mastromarino, P., Pan'a, A., Superti, F. &. Orsi, N. (1983) Activity of human serum lipoproteins the infectivity of rhabdoviruses. Microbiology 6: 91-99.
on
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11. Grunfeld, C., Soued, M., Adi, S., Moser, A. H., Dinarello, C. A. & Feingold, K. R. (1990) Evidence for two classes of cytokines that stimulate hepatic lipogenesis: Relationships among tumor necrosis factor, interleukin-1 and interferon-alpha. Endocrinol ogy 127: 46-54. 12. Grunfeld, C., Soued, M., Adi, S., Moser, A. H., Fiers, W., Di narello, C. A. & Feingold, K. R. (1991) Interleukin-4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin-1 and interleukin-6 but not by interferon-alpha. Cancer Res. 51: 2803-2807. lì.Cerami, A., Ikeda, Y., Latrang, N., Hotez, P. G. A. & Beutler, B. (1985) Weight loss associated with an endotoxin induced mediator from peritoneal macrophages: The role of cachectin (tumor necrosis factor). Immunol. Lett. 11: 173-177.
AND AIDS
and AIDS
CARL GRÃœNFELD3 AND KENNETH R. FEINGOLD Department of Medicine, University of California, San Francisco, CA and Metabolism Section Department of Veterans Affairs Medical Center, San Francisco, CA 94121 (7). A single factor (named cachectin) that might me diate both hypertriglyceridemia and wasting was ten tatively identified as tumor necrosis factor (TNF). An initial report that TNF levels were elevated in AIDS patients (8) led to the conclusion that TNF was the cause of cachexia in AIDS. However, as will be outlined below, the metabolic disturbances that occur during infection are more complex than originally hypothesized and are not due to a single cytokine. Further, the hypertriglyceridemia of infection is not mechanistically linked to cachexia; instead, hypertriglyceridemia may play a role in host defense.
ABSTRACT The hypertriglyceridemia of infection is mediated by many of the cytokines that regulate the immune response, including the tumor necrosis factors, the interleukins and the interferons. In the acquired immunodeficiency syndrome (AIDS),4 hypertriglycer idemia is most likely due to increased circulating levels of interferon alpha. Both in AIDS and in animal models there is no direct association between the presence of hypertriglyceridemia and the syndrome of wasting. Rather, circulating lipoproteins may neutralize infec tious organisms and therefore contribute to host defense. J. Nutr. 122: 749-753, 1992. INDEXING KEY WORDS:
•acquired immunodeficiency syndrome •cytokines •lipids •cachexia •infection
TNF AND LIPID METABOLISM IN VIVO Administration of TNF to rats induces a rapid in crease in plasma TG due to VLDL of normal compo-
Hypertriglyceridemia commonly occurs during in fection (1). Early studies indicated three mechanisms by which infection might increase triglycérides(TG)4: 1} Increased hepatic de novo synthesis of fatty acids (FA)leading to increased secretion of very low density lipoprotein (VLDL) (2). 2) Increased adipose tissue lipolysis with the mobilized FA being reesterified into TG in the liver and then resecreted as VLDL rather than being oxidized (3). 3) Decreased levels of lipo protein Upase (LPL)leading to decreased clearance of TG-rich lipoproteins (4, 5). These changes are thought to be mediated by cytokines secreted by the host in response to infection (6). It is also thought that the cachexia associated with infection is due to cytokines. Because hypertriglyc eridemia and cachexia may occur simultaneously dur ing infection (5), it was originally proposed that a sin gle factor caused both cachexia and hypertriglyceride mia by decreasing the storage of fat in adipose tissue
1Presented as part of a symposium: Nutrition, Immunomodulation and AIDS, given at the 75th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlanta, GA, April 25, 1991. The symposium was sponsored by the American Institute of Nutrition and supported in part by grants from Campbell Institute for Research and Technology, Clintgec International Inc., BristolMyers Company and Mead Johnson Research Center. Guest editor for this symposium was R. R. Watson, Department of Family and Community Medicine, University of Arizona, Tucson, AZ. 2This work was supported by grants from the Department of Veterans Affairs, the Universitywide AIDS Research Program of the University of California and the National Institutes of Health (DK-40990|. Dr. Grunfeld is a recipient of a Clinical Investigator Award from the Department of Veterans Affairs. 3To whom correspondence should be addressed: Metabolism Section (11IF), VA Medical Center, 4150 Clement Street, San Fran cisco, CA 94121. 4Abbreviations: TG, triglycéride; LPS,endotoxin,-AIDS, acquired immunodeficiency syndrome; HIV, human immunodeficiency virus; TNF, tumor necrosis factor; IL, interleukin; IFN, interferon; VLDL, very low density lipoprotein; HDL, high density lipoprotein; LDL, low density lipoprotein; LPL lipoprotein lipase; FA, fatty acid.
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The Role of the Cytokines, Interferon Alpha and Tumor Necrosis Factor in the Hypertriglyceridemia and Wasting of AIDS12
750
GRUNFELD
OTHER
CYTOKINES INFLUENCE METABOLISM IN VIVO
LIPID
In mice, TNF, interleukin (IL)-l, IL-6 and interferon (IFN) alpha all increase hepatic FA synthesis within 30 min of administration, with the increase for most
cytokines being sustained for many hours (6). It is of interest that the doses for stimulation of hepatic FA synthesis by TNF and IL-1 are similar to the doses that produce fever (endogenous pyrogen activity). There fore, cytokine-stimulated hepatic lipogenesis should occur under physiological conditions of infection that produce TNF or IL-1 (6). Studies on the mechanism of the stimulation of he patic FA synthesis suggested that there are two classes of lipogenic cytokines. TNF, IL-1 and IL-6 stimulate hepatic FA synthesis by increasing hepatic levels of citrate, the major allosteric activator of acetyl CoA carboxylase, the rate-limiting enzyme for FA synthesis (11). In contrast, IFN alpha works by a different and as yet unknown mechanism (11). Administration of IFN alpha with either TNF or IL-1 in low doses pro duces synergy whereas high doses lead to additivity in stimulating hepatic lipogenesis. On the other hand, there is no synergy or additivity when two cytokines from the same class (TNF and IL-1) are given simul taneously. IL-4 is a cytokine that shows inhibitory properties during the immune response. IL-4 administered alone has no effect on hepatic FA synthesis, but IL-4 inhibits the ability of TNF, IL-1 and IL-6 to stimulate hepatic lipogenesis (12). IL-4 counteracts the ability of cyto kines to increase hepatic citrate levels. As a conse quence, IL-4 is unable to block IFN-alpha-stimulated hepatic lipogenesis, confirming the two classes of li pogenic cytokines.
ARE CYTOKINE INDUCED CHANGES LIPID METABOLISM THE CAUSE OF CACHEXIA?
IN
It was originally proposed that cachectin (TNF) in duced both cachexia and hypertriglyceridemia through its effects on the fat cell; by decreasing LPL,TNF might decrease TG clearance and inhibit the storage of fat in adipose cells (7). Thus, the induction of hypertri glyceridemia and cachexia were proposed to be mech anistically linked. A large body of experimental data raised questions about this hypothesis. 1)If the ability to induce a catabolic state in cultured fat cells is the criterion for being cachectin, then IL-1 and the IFNs (which decrease the storage and promote the break down of TG in cultured fat cells in a manner similar to TNF) could equally be classified as cachectins (6). 2)TNF does not appear to have similar catabolic effects in cultured fat cells from rats or humans (6). 3) The catabolic effects that TNF induces in cultured fat cells do not occur in vivo. TNF does not increase plasma TG in rats by decreasing TG clearance and storage; rather, TNF increases hepatic lipogenesis and VLDL production. Additionally, there is no effect of TNF on adipose tissue FA synthesis in vivo (6).
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sition; plasma chylomicron levels were not increased in fed rats (6). Plasma TG remain elevated for 17 h as the VLDL is processed to TG-rich low density lipoprotein (LDL).Plasma TG are also increased in humans given TNF (9). Initial studies with crude cachectin (7) and, subse quently, recombinant TNF (6) showed that TNF re duced LPLactivity in cultured 3T3-L1 mouse fat cells. Therefore, TNF could potentially increase plasma TG by decreasing LPL, causing decreased clearance (stor age) of TG-rich lipoproteins. Although TNF does de crease LPL in epididymal fat pads of mice, rats and guinea pigs, this decrease requires several hours, sim ilar to the time course of TNF in 3T3-L1 cells (6). However, plasma TG rise within 45 min of adminis tration of TNF. More important, TNF does not sig nificantly decrease LPL activity in multiple other adi pose tissue sites or in muscle, and TNF increases total plasma postheparin lipase. As a consequence, TNF has no effect on the clearance of VLDL or chylomicron TG. These data raise questions as to whether cultured 3T3-L1 cells are a valid model for the effects of cytokines in vivo. Rather, TNF produces hypertriglyceridemia by rapidly increasing the VLDL production rate (6). TNF increases hepatic de novo FA synthesis and total he patic TG synthesis with newly synthesized TG ap pearing in plasma. TNF also rapidly (within 90 min) mobilizes FA from the periphery (10), which again is different from TNF-stimulated lipolysis in cultured fat cells, which requires several hours. During fasting, exercise or stress, mobilized FA are oxidized by the liver, but during infection they may be incorporated into hepatic TG and secreted as VLDL (3). TNF can induce similar reesterification of peripherally derived FA. When TNF-induced lipolysis is inhibited in vivo by the antilipolytic drug phenylisopropyladenosine, there is significant blunting of the TNF-induced in crease in serum TG (10). Thus, in chow-fed animals, the increase in hepatic VLDL production and plasma TG induced by TNF is due to a combination of in creased de novo hepatic FA synthesis and increased reesterification of peripherally derived FA. However, dietary conditions can influence the source of FA for TG synthesis. In sucrose-fed rats, where the basal rates of hepatic FA synthesis are markedly increased, TNF does not stimulate lipolysis and the TNF-induced in crease in the hepatic FA synthetic rate provides ade quate FA for induction of hypertriglyceridemia.
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that the hypertriglyceridemia of infection is not in evitably or mechanistically linked to the induction of cachexia as was originally proposed in the cachectin hypothesis. Human disease may have both hypertri glyceridemia and cachexia, but there is no evidence that the two are mechanistically linked (see below).
LIPIDS AND LIPOPROTEINS
IN AIDS
Serum TG levels in subjects with AIDS average twice that of controls (30, 31). Serum TG in subjects with HIV infection fall in between control and AIDS patients depending upon where the subjects are in the time course between asymptomatic HIV infection and development of AIDS. In contrast, serum cholesterol levels are decreased equally in both AIDS and HIVpositive subjects (unpublished data). Decreases are seen in high density lipoprotein (HDL) and LDL cho lesterol, apo B-100 (primarily found in LDL) and apo A-l (primarily found in HDL). When lipoprotein composition was analyzed, there was an increase in VLDL of normal composition in AIDS, whereas LDL and HDL were slightly TG-rich (unpublished data). As a consequence, the increase in plasma TG was almost entirely due to the increase in VLDL.
LACK OF CORRELATION BETWEEN HYPERTRIGLYCERIDEMIA AND WASTING IN AIDS Serum lipids were studied in subjects whose body composition had been studied (30). Half of the subjects with AIDS and HIV infection had hypertriglyceride mia and half showed wasting as determined by mea surement of total body potassium (30). However, there was no relationship between levels of serum TG and wasting in these subjects with AIDS and HIV infec tion. Patients with wasting had similar TG levels and prevalence of hypertriglyceridemia as those without wasting. Many patients were sequentially followed with time. Most of the patients with persistent hypertri glyceridemia showed prolonged periods of stable weight and lean body cell mass over several months (30). Thus, as seen in animal models, hypertriglycer idemia in human infection is not inevitably linked to the wasting syndrome.
CIRCULATING CYTOKINE LEVELS IN AIDS Multiple studies have found increased circulating IFN alpha levels in subjects with AIDS (see réf. 31 for
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Lastly and most important, TNF does not induce cachexia in the same way that was seen with crude cachectin [supernatants from endotoxin (LPS)-stimulated macrophages]. Daily injections of the same dose of crude cachectin produced persistent weight loss (13). In contrast, daily injection of the same dose of purified recombinant TNF leads to acute weight loss due to anorexia and negative fluid balance, but mul tiple laboratories have found that, with repeated in jections of the same dose of TNF, animals rapidly re cover from anorexia and gain weight back to the level of control animals (14-23). Because of the disappointing failure of TNF to mimic crude cachectin in inducing the syndrome of cachexia, other models had been developed in which TNF administration is associated with chronic weight loss. First, sequential escalation of TNF doses to levels that would initially be lethal can produce chronic weight loss in rodents, but this weight loss is also mostly due to anorexia and is similar to pair-fed ani mals (16). Other models for TNF induced anorexia/ cachexia are likely to require synergistic interactions between cytokines, such as we have found for lipogenesis. For example, catheterized rats show persistent anorexia and weight loss when chronically infused with TNF (24). However, chronically catheterized rats do not grow at normal rates, suggesting that inflam matory products generated at the catheterization site are already having physiological effects; these products could interact with TNF to produce weight loss. In addition, weight loss during continuous TNF infusion is also similar to that of pair-fed rats (24). Finally, a tumor genetically engineered to produce TNF causes weight loss when implanted into animals (25), but the interactions of TNF with other tumor products or with substances produced by host cells that have infiltrated the tumor have not been explored. Tumor-bearing an imals are known to be more susceptible to the toxic effects of TNF (26). In summary, administration of pure TNF alone does not reproduce the original syn drome of wasting that was found with crude cachectin, but TNF may contribute to cachexia when produced in conjunction with other mediators of the immune or inflammatory response, just as synergy is seen be tween TNF and IFN alpha in stimulating lipogenesis. Unlike the tachyphyllaxis to TNF, injection of IL-1 produces sustained anorexia and weight loss (27, 28). Treatment of cancer patients with IFN may also produce anorexia. Other as yet to be identified cyto kines may play important roles in the induction of cachexia, especially in promoting muscle protein deg radation (29). Although animals develop resistance to the anorectic effects of TNF during repeated administration, this is not a general resistance to all of TNF's activities. Chronic TNF administration leads to persistent ele vations in plasma TG in animals that have resumed eating and regained their weight (21).These data imply
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GRUNFELD
IFN ALPHA DRIVES HYPERTRIGLYCERIDEMIA IN AIDS Given the difficulty in detecting elevations of serum TNF in AIDS it is not surprising that there is no cor relation between plasma TG and serum TNF levels (31). On the other hand, serum TG levels are correlated at a highly significant level (r = 0.446, P < 0.002) with IFN alpha levels. When patients were followed se quentially with time, their TG levels paralleled their IFN alpha levels. The mechanisms by which IFN alpha affects TGs in AIDS have recently been studied. LPL is decreased in subjects with AIDS and HIV infection (unpublished data). As a consequence, the clearance of TG from plasma is significantly slowed. In addition, there is a striking correlation (r = 0.783, P < 0.001) between serum IFN alpha levels and the change in TG clearance ip AIDS. Therefore, even under conditions where a cytokine might slow the clearance (hence storage) of TG, there is no direct link between those disturbances in lipid metabolism and wasting. Preliminary unpublished data also indicate that de novo hepatic FA synthesis is increased in subjects with HIV infection. A significant correlation was also found between basal rates of FA synthesis and circulating IFN alpha levels.
WHY DO DISTURBANCES IN LIPID METABOLISM OCCUR DURING INFECTION? The data presented above indicate that there is no direct association between disturbances of lipid or lipoprotein metabolism and wasting during infection. Yet these disturbances in lipid metabolism commonly occur in multiple types of infections (see réf.6 for review). The data presented above indicate that dis turbances in lipid metabolism are tightly linked to cytokines and the immunological response; multiple cytokines at low doses modulate the effect of lipid me tabolism through multiple receptors at multiple sites and by multiple mechanisms. The question must therefore be raised as to whether disturbances in lipid
metabolism could be beneficial to the host as part of the hepatic acute phase response. There are multiple lines of evidence that plasma lipoproteins can decrease the toxicity of microorgan isms. VLDL, LDL and HDL can bind LPSand decrease or prevent the ability of LPSto induce fever, hypoten sion and death in mice and rats (35, 36). In these stud ies lipoproteins and LPS were preincubated in vitro with lipoprotein-depleted plasma present. Although the ability of lipoproteins to detoxify LPS in vivo has not yet been demonstrated, there is evidence that VLDL from normal subjects contains bound and se questered LPS (36). Lipoproteins have also been shown to bind and/or neutralize multiple viruses, including mouse retroviruses (37), Epstein-Barr virus (38), Japanese encepha litis virus (39), rabies virus and vesicular stomatitis virus (40). Increased production of VLDL is a prominent dis turbance in lipid metabolism that occurs during in fection. There is no direct linkage between hypertriglyceridemia during infection and the wasting syn drome. However, lipoproteins may inactivate infectious agents. The body's ability to increase TG production represents a part of the acute phase re sponse that serves to maintain levels of protective li poproteins during infection.
LITERATURE CITED 1. Beisel, W. R. (1975) Metabolic response to infection. Annu. Rev. Med. 26: 9-20. 2. Guckian, J. D. (1973) Role of metabolism in pathogenesis of bacteremia due to Diplococcus pneumoniae in rabbits. J. Infect. Dis. 127: 1-8. 3. Wolfe, R. R., Shaw, J. H. F. & Durkot, M. J. (1985) Effect of sepsis on VLDL kinetics: Responses in basal state and during glucose infusion. Am. J. Physiol. 248: E732-E740. 4. Kaufmann, R. L., Maison, C. F. &. Beisel, W. R. (1976) Hypertriglyceridemia produced by endotoxin: Role of impaired trilyceride disposal mechanisms. J. Infect. Dis. 133: 548-555. 5. Rouzer, C. A. & Cerami, A. (1980) Hypertriglyceridemia as sociated with Trypanosoma bruceii bruceii infection in rabbits: Relative effect of triglycérideremoval. Mol. Biochem. Parasitol. 2:31-38. 6. Grunfeld, C. &. Feingold, K. R. (1991) The metabolic effects of tumor necrosis factor. Biotherapy 3: 143-148. 7. Beutler, B. & Cerami, A. (1986) Cachectin and tumor necrosis factor as two sides of the same biological coin. Nature 320: 584-588. 8. Lahdevirta, K., Maury, C. P. J., Teppo, A. M. & Repo, H. (1988) Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am. J. Med. 85:289-291. 9. Starnes, F., Jr., Warren, R. S., Jeevanandam, M.; Gabrilove, J. L, Larchian, W., Oettgen, H. F. & Brenman, M. E. (1988) Tumor necrosis factor and the acute metabolic response to in jury. J. Clin. Invest. 82: 1321-1325. 10. Feingold, K. R., Adi, S., Staprans, I., Moser, A. H., Neese, R., Verdier, J. A., Doerrler, W. & Grunfeld, C. (1990) Diet affects the mechanism by which TNF stimulates hepatic triglycéride production. Am. J. Physiol. 259: E177-E184.
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review). In fact, IFN alpha appears at about the time of the transition from asymptomatic HIV infection to AIDS. Although an initial study reported increased levels of TNF in AIDS (8), no significant differences in TNF levels had been found between AIDS and controls in six other cohorts of patients (31-34, unpublished data). Many AIDS patients in the first report (8)were studied during acute opportunistic infections, which may ac count for the ability to detect TNF in serum.
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14. Patton, J. S., Peters, P. M., McCabe, J., Grase, D., Hansen, S., & Chen, A. B. (1987) Development of partial tolerance to the gastrointestinal effects of high doses of recombinant tumor ne crosis factor alpha in rodents. J. Clin. Invest. 80: 1587-1596. 15. Moldawer, L. L., Suaniger, G., Gelin, G. &. Lundholm, K. G. (1987) Interleukin-1 and tumor necrosis factor do not regulate protein balance in skeletal muscle. Am. J. Physiol. 253: C766C773. 16. Tracey, K. G., Wei, H., Manogue, K. R., Fary, Y., Hesse, D. G., Nguyen, H. T., Juo, G. C., Beutler, B., Cotran, R. S., Cerami, A. & Lowry, S. F. (1988) Cachectin/tumor necrosis factor in duces cachexia, anemia and inflammation. J. Exp. Med. 167: 1211-1227. 17. Kettelhut, I. C. & Goldberg, A. L. (1988) Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue. J. Clin. Invest. 81: 13841389. 18. Socher,S. H., Friedman, A. & Martinez, D. (1988) Recombinant human-tumor necrosis factor induces acute reductions in foodintake and body-weight in mice. J. Exp. Med. 167: 1957-1962. 19. Stovroff, M. C., Fraker, D. L., Swedenborg, J. A. & Norton, J. A. (1988) Cachectin/tumor necrosis factor; a possible me diator of cancer anorexia in the rat. Cancer Res. 48: 4567-4572. 20. Kramer, S. M., Aggarwal, B. B., Essalu, T. E., McCabe, T. E., Ferraiolo, B. C., Figari, I. S. & Palladino, M. A., Jr. (1988) Characterization of the in vitro and in vivo species preference of human murine tumor necrosis factor alpha. Cancer Res. 48: 920-925. 21. Grunfeld, C., Wilking, H., Neese, R., Gavin, L. A., Moser, A. H., Culli, R., Serio, M. K. & Feingold, K. F. (1989) Per sistence of the hypertriglyceridemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/ cachectic effects in rats. Cancer Res. 49: 2554-2560. 22. Mahoney, S. M. &. Tisdale, M. J. (1989) Reversal of weight loss induced by tumor necrosis factor. Cancer Lett. 45: 167172. 23. Mullen, B. J., Harris, R. B. S., Patton, J. S. & Martin, R. J. (1990) Recombinant tumor necrosis factor alpha chronically administered in rats: Lack of cachectic effects. Proc. Soc. Exp. Biol. Med. 193: 318-325. 24. Michie, H. R., Sherman, M. L., Spriggs, D. R., Rounds, J., Chris tie, M. & Wilmore, D.W. (1989) Chronic TNF infusion causes anorexia but not accelerated nitrogen loss. Ann. Surg. 209: 1924.
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25. Oliff, A., Defeo-Jones, D., Boyer, M., Martinez, D., Kiefer, D., Vuocolo, G., Wolfe, A. & Sector, S. H. (1987) Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50: 555563. 26. Bartholeyns, J., Freudenberg, M. & Galanos, C. (1987) Growing tumors induce hypersensitivity to endotoxin and tumor necrosis factor. Infect. Immun. 55: 2230-2233. 27. Fujii, T., Sato, K., Ozawa, M., Kasano, K., Imamura, H., Kanaji, Y., Tsushima, T. & Shizume, K. (1989) Effect of interleukin-1 (IL-1) on tyroid hormone metabolism in mice: Stimulation by IL-1 of iodothyronine S'-deiodinating activity (Type I) in the liver. Endocrinology 124: 167-174. 28. Hellerstein, M. K., Meydani, S. N., Meydani, M., Wu, K. & Dinarello, C. A. (1989) Interleukin-1 induced anorexia in the rat. J. Clin. Invest. 84: 228-235. 2?. Goldberg, A. L., Kettelhut, I. C., Fonano, K., Egan, J. M. a Baracos, V. (1988) Activation of protein breakdown and prostaglandin E2production in rat skeletal muscle in fever is signaled by a macrophage product distinct from interleukin-1 or known cytokines. J. Clin. Invest. 81: 1378-1383. 30. Grunfeld, C., Kotler, D. P., Hamadeh, R., Tierney, A., Wang, J., Pierson, M. A., Jr. (1989) Hypertriglyceridemia in the ac quired immunodeficiency syndrome. Am. J. Med. 86: 27-31. 31. Grunfeld, C., Kotler, D. P., Shigenaga, J. K., Doerrler, W., Tier ney, A., Wang, J., Pierson, R. N. & Feingold, K. R. (1991) Circulating interferon alpha levels and hypertriglyceridemia in the acquired immunodeficiency syndrome. Am. J. Med. 90: 154162. 32. Reddy, M. M., Sorrell, S. J., Lange, M. & Grieco, M. H. (1988) Tumor necrosis factor and HIV P24 antigen serum of HIV-infected population. J. AIDS 1: 436-440. 33. Hommes, M., Romijin, J. A., Godfried, M. H., Eeftinck Schattenkerk, J. K. M., Burrman, W. A., Enden, E. & Sauerwein, H. P. (1990) Increased resting energy expenditure in human immunodeficiency virus-infected men. Metabolism 39: 11861190. 34. Dworkin, B., Seaton, T. &Wormsef, A. (1990) Tumor necrosis factor (TNF), metabolic rate, body composition and weight loss in HIV infected patients. Clin. Res. 38: 361A(abs.). 35. Ulevitch, R. J., Johnston, A. R. & Weinstein, D. B. (1979) New function for high density lipoproteins. Their participation in intravascular reactions of bacterial lipopolysaccharides. J. Clin. Invest. 64: 1516-1524. 36. Harris, H. W., Grunfeld, C., Feingold, K. R. & Rapp, J. H. (1990) Human VLDL and chylomicrons can protect against endotoxin-induced death in mice. J. Clin. Invest. 86: 696-792. 37. Sernatinger, J., Hoffman, A., Harman, D., Kane, J. P. & Levy, J. A. (1988) Neutralization of mouse xenotropic virus by li poproteins involves binding to the virions. J. Gen. Virol. 69: 2651-2661. 38. Chisari, F. V., Curtiss, L. K. & Jensen, F. C. (1981) Physiologic concentrations of normal human plasma lipoproteins inhibit the immortalization of peripheral B lymphocytes by the EpsteinBarr virus. J. Clin. Invest. 68: 329-336. 3».Shortridge, K. F., Ho, W. K., Oya, A. & Kobayashi, M. (1975) Studies on the inhibitory activities of human serum lipoproteins for Japanese encephalitis virus. Southeast Asian J. Trop. Med. Public Health 6: 461-466. 40. Seganti, L., Grassi, M., Mastromarino, P., Pan'a, A., Superti, F. &. Orsi, N. (1983) Activity of human serum lipoproteins the infectivity of rhabdoviruses. Microbiology 6: 91-99.
on
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11. Grunfeld, C., Soued, M., Adi, S., Moser, A. H., Dinarello, C. A. & Feingold, K. R. (1990) Evidence for two classes of cytokines that stimulate hepatic lipogenesis: Relationships among tumor necrosis factor, interleukin-1 and interferon-alpha. Endocrinol ogy 127: 46-54. 12. Grunfeld, C., Soued, M., Adi, S., Moser, A. H., Fiers, W., Di narello, C. A. & Feingold, K. R. (1991) Interleukin-4 inhibits stimulation of hepatic lipogenesis by tumor necrosis factor, interleukin-1 and interleukin-6 but not by interferon-alpha. Cancer Res. 51: 2803-2807. lì.Cerami, A., Ikeda, Y., Latrang, N., Hotez, P. G. A. & Beutler, B. (1985) Weight loss associated with an endotoxin induced mediator from peritoneal macrophages: The role of cachectin (tumor necrosis factor). Immunol. Lett. 11: 173-177.
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