Maruo et al.
JR, ed. Endocrinology of pregnancy. Chicago: Year Book, 1981:1-34. 19. Maruo T, Matsuo H, Hayashi M, Nishino R, Mochizuki M. Induction of differentiated trophoblast function by epidermal growth factor: relation of immunohistochemically detected cellular epidermal growth factor receptor levels. J Clin Endocrinol Metab 1987;64:744-9. 20. Ladines-Llave CA, Maruo T, Manalo AS, Mochizuki M. Cytologic localization of epidermal growth factor and its
July 1992 Am J Obstet Gynecol
receptor in developing human placenta varies over the course of pregnancy. AM J OBSTET GVNECOL 1991; 165: 1377-82. 21. Kao LC, Caltabiano S, Wu S, Strauss JF III, Kliman Hl The human villous cytotrophoblast: interactions with extracellular matrix proteins, endocrine function and cytoplasmic differentiation in the absence of syncytium formation. Dev Bioi 1988; 130:693-702.
Transforming growth factor-J3 opposes the stimulatory effects of interleukin-l and tumor necrosis factor on amnion cell prostaglandin E2 production: Implication for preterm labor Kristina Bry, MD, and Mikko Hallman, MD Irvine, California, and Helsinki, Finland OBJECTIVE: In preterm labor increased concentrations of interleukin-' and tumor necrosis factor are present in amniotic fluid. These cytokines may promote labor by stimulating the production of prostaglandins by intrauterine tissues. In many biologic processes, transforming growth factor-13 modifies the actions of cytokines. We studied the effect of transforming growth factor-J3 on the cytokine-induced prostaglandin E2 production by amnion cells. STUDY DESIGN: Human amnion cells in monolayer culture were treated with interleukin-1, tumor necrosis factor, or vehicle in the presence or absence of transforming growth factor-I3. The prostaglandin E2 production was measured. RESULTS: Transforming growth factor-13 decreased the interleukin-1- or tumor necrosis factor-induced prostaglandin E2 production by 70% to 80% and the basal prostaglandin E2 synthesis by 27%. The synergistic stimulation of prostaglandin E2 production by the combination of interleukin-1 with tumor necrosis factor was inhibited by 80% in cells treated with transforming growth faclor-l3. Transforming growth factor-j31, -132, and -131,2 were equipotent. CONCLUSION: Transforming growth factor-j3 suppresses the cytokine-induced prostaglandin E2 production by amnion cells and may be an important factor in maintaining pregnancy in the face of labor-promoting cytokines. (AM J OBSTET GVNECOL 1992;167:222-6.)
Key words: Preterm labor, prostaglandins, interleukin-l, tumor necrosis factor, transforming growth factor-/3, fetal membranes Preterm labor often occurs in the setting of intrauterine infection. I The concentrations of cytokines such as interleukin-l (IL-l) and tumor necrosis factor (TNF) increase in amniotic fluid in pre term labor.2~4 ProstaFrom the Department of Pediatrics, University of California, [rome, and the Department of Pediatrics, University of Helsinki. Supported by the Foundation for Maternal and Infant Care and the Sigrid Juselius Foundation. Received for publication October 14, 1991; revised January 21, 1992; accepted January 23,1992. Reprint requests: Kristina Bry, MD, DepaTtment of Pediatrics, University of California, Imine, Med. SUTge /.. Rm 109 F, [mine, CA 92717. 611/36682
222
gland ins, major inducers of uterine contractions, are produced by intrauterine tissues in response to these cytokines. 3 5·7 The amnion, which produces almost exclusively prostaglandin £2 (PG£2),8 is an important intrauterine source of prostaglandin. The combination of [L-l with TNF has a synergistic stimulator effect on the PGE 2 production by human amnion cells in culture.~ IL-I and TNF have been implicated in the induction of preterm labor associated with infections."' 3, 10 Transforming growth fac10r-/3 (TGF-/3) represents a family of multifunctional factors that influence cell growth, differentiation, immunity, and extracellular matrix formation. II Several forms of TGF -/3 and of
TGF·jj, PGE 2 production, and labor 223
Volume 167 Number 1
-
--0--
no TGF·B1
~
TGF·B1 (10 ng/ml)
0.6
0.4
c:(
Z
0.5
Cl
0.4
C
c -...
-
0.3
Cl Q.
0.2
0.3
N
W
(!)
c..
0.2 0.1 0.1 0.0
0
.05
.5
TNF- (X
5
50
500
5000
0.0
0
.005
0.5
.05
IL-1B
(ng/ml)
5
50
500
(ng/ml)
Fig. 1. Effect of TGF-jj on amnion cells stimulated with different concentrations of TNF-a or ILIjj. Human amnion cells were treated with indicated concentrations ofTNF-a or IL-Ijj in presence (e) or absence (0) of human TGF-jj\ (10 ng/ml). PGE 2 production (picograms per nanogram DNA) was measured after 42-hour incubation. Results are means ± SE (n = 4) of one representative experiment.
their receptors have been identified. TGF-J31 and TGF132 are homodimers, and TGF -131,2 is a heterodimer containing one polypeptide chain each from TGF-J31 and TGF-J32. Most tissues found at the maternal-fetal interface contain TGF-J3 and express TGF-J3 messenger ribonucleic acid.'2 In many biologic processes, TGF-J3 acts as a biologic switch, antagonizing or modifying the action of other growth factors or cytokines. 13 We therefore studied the effect of TGF-(3 on the cytokine-induced PGE 2 production by human amnion cells in culture. In this report we show that TGF-J3 suppresses the IL-l- or TNF-stimulated PGE 2 production by amnion cells.
Material and methods Chemicals. Recombinant human TNF-a (specific activity 4.8 x 10 7 U I mg, endotoxin content
JR, ed. Endocrinology of pregnancy. Chicago: Year Book, 1981:1-34. 19. Maruo T, Matsuo H, Hayashi M, Nishino R, Mochizuki M. Induction of differentiated trophoblast function by epidermal growth factor: relation of immunohistochemically detected cellular epidermal growth factor receptor levels. J Clin Endocrinol Metab 1987;64:744-9. 20. Ladines-Llave CA, Maruo T, Manalo AS, Mochizuki M. Cytologic localization of epidermal growth factor and its
July 1992 Am J Obstet Gynecol
receptor in developing human placenta varies over the course of pregnancy. AM J OBSTET GVNECOL 1991; 165: 1377-82. 21. Kao LC, Caltabiano S, Wu S, Strauss JF III, Kliman Hl The human villous cytotrophoblast: interactions with extracellular matrix proteins, endocrine function and cytoplasmic differentiation in the absence of syncytium formation. Dev Bioi 1988; 130:693-702.
Transforming growth factor-J3 opposes the stimulatory effects of interleukin-l and tumor necrosis factor on amnion cell prostaglandin E2 production: Implication for preterm labor Kristina Bry, MD, and Mikko Hallman, MD Irvine, California, and Helsinki, Finland OBJECTIVE: In preterm labor increased concentrations of interleukin-' and tumor necrosis factor are present in amniotic fluid. These cytokines may promote labor by stimulating the production of prostaglandins by intrauterine tissues. In many biologic processes, transforming growth factor-13 modifies the actions of cytokines. We studied the effect of transforming growth factor-J3 on the cytokine-induced prostaglandin E2 production by amnion cells. STUDY DESIGN: Human amnion cells in monolayer culture were treated with interleukin-1, tumor necrosis factor, or vehicle in the presence or absence of transforming growth factor-I3. The prostaglandin E2 production was measured. RESULTS: Transforming growth factor-13 decreased the interleukin-1- or tumor necrosis factor-induced prostaglandin E2 production by 70% to 80% and the basal prostaglandin E2 synthesis by 27%. The synergistic stimulation of prostaglandin E2 production by the combination of interleukin-1 with tumor necrosis factor was inhibited by 80% in cells treated with transforming growth faclor-l3. Transforming growth factor-j31, -132, and -131,2 were equipotent. CONCLUSION: Transforming growth factor-j3 suppresses the cytokine-induced prostaglandin E2 production by amnion cells and may be an important factor in maintaining pregnancy in the face of labor-promoting cytokines. (AM J OBSTET GVNECOL 1992;167:222-6.)
Key words: Preterm labor, prostaglandins, interleukin-l, tumor necrosis factor, transforming growth factor-/3, fetal membranes Preterm labor often occurs in the setting of intrauterine infection. I The concentrations of cytokines such as interleukin-l (IL-l) and tumor necrosis factor (TNF) increase in amniotic fluid in pre term labor.2~4 ProstaFrom the Department of Pediatrics, University of California, [rome, and the Department of Pediatrics, University of Helsinki. Supported by the Foundation for Maternal and Infant Care and the Sigrid Juselius Foundation. Received for publication October 14, 1991; revised January 21, 1992; accepted January 23,1992. Reprint requests: Kristina Bry, MD, DepaTtment of Pediatrics, University of California, Imine, Med. SUTge /.. Rm 109 F, [mine, CA 92717. 611/36682
222
gland ins, major inducers of uterine contractions, are produced by intrauterine tissues in response to these cytokines. 3 5·7 The amnion, which produces almost exclusively prostaglandin £2 (PG£2),8 is an important intrauterine source of prostaglandin. The combination of [L-l with TNF has a synergistic stimulator effect on the PGE 2 production by human amnion cells in culture.~ IL-I and TNF have been implicated in the induction of preterm labor associated with infections."' 3, 10 Transforming growth fac10r-/3 (TGF-/3) represents a family of multifunctional factors that influence cell growth, differentiation, immunity, and extracellular matrix formation. II Several forms of TGF -/3 and of
TGF·jj, PGE 2 production, and labor 223
Volume 167 Number 1
-
--0--
no TGF·B1
~
TGF·B1 (10 ng/ml)
0.6
0.4
c:(
Z
0.5
Cl
0.4
C
c -...
-
0.3
Cl Q.
0.2
0.3
N
W
(!)
c..
0.2 0.1 0.1 0.0
0
.05
.5
TNF- (X
5
50
500
5000
0.0
0
.005
0.5
.05
IL-1B
(ng/ml)
5
50
500
(ng/ml)
Fig. 1. Effect of TGF-jj on amnion cells stimulated with different concentrations of TNF-a or ILIjj. Human amnion cells were treated with indicated concentrations ofTNF-a or IL-Ijj in presence (e) or absence (0) of human TGF-jj\ (10 ng/ml). PGE 2 production (picograms per nanogram DNA) was measured after 42-hour incubation. Results are means ± SE (n = 4) of one representative experiment.
their receptors have been identified. TGF-J31 and TGF132 are homodimers, and TGF -131,2 is a heterodimer containing one polypeptide chain each from TGF-J31 and TGF-J32. Most tissues found at the maternal-fetal interface contain TGF-J3 and express TGF-J3 messenger ribonucleic acid.'2 In many biologic processes, TGF-J3 acts as a biologic switch, antagonizing or modifying the action of other growth factors or cytokines. 13 We therefore studied the effect of TGF-(3 on the cytokine-induced PGE 2 production by human amnion cells in culture. In this report we show that TGF-J3 suppresses the IL-l- or TNF-stimulated PGE 2 production by amnion cells.
Material and methods Chemicals. Recombinant human TNF-a (specific activity 4.8 x 10 7 U I mg, endotoxin content
