Chemotactic cytokines in the epidemiis Schroder J-M. Chemotactic cytokines in the epidermis. Exp Dermatol 1992: 1: 12-19.

Jens-Michael Schroder Depattment of Detmatology, University of Kiel, Kiel, Germany

Key wotds: cytokines; epidermis Jens-Michael Schtbdet, Depl. o( Dermatology, tJniversify of Kiel, Schitlenhelmstr. 7, D-2300, Kiel, Germany. Accepted tor publication 30 March 1992

Introduction In a variety of inflammatory skin disorders the pattern of histologieally deteetable leukocyte forms and subsets in the affected tissue often is characteristic for the type or stage of the skin disease. This elinieal observation raises the question as to whieh faetors determine the appearance and eomposition of leukoeyte tissue inftltrates. Skin diseases such as psoriasis, whieh show a preferential epidermal infiltration by neutrophils and T lymphocytes, appeared to be model inflammatory diseases for testing the hypothesis that generation of leukoeyte ehemotaetie faetors (ehemotaxins) oeeurs in vivo in the tissue: Langhof & Muller in 1966 were the first to deseribe that neutrophils were attracted in vitro by mixtures of psoriatie seales and serum (1). More detailed investigations later led to the conclusion that neutrophil attraetants present in psoriatie lesions appeared to be eomplement-derived (2), and therefore are not tissue cell-derived but blood-borne. With the deteetion of lipid attraetants like the potent chemotaxin leukotriene B4 (3), platelet activating faetor (4) and the low potency ehemotaetie lipid 12-hydroxyeieosatetraenoie aeid (12-HETE) in lesional epidermis or seales obtained from psoriatie patients (5) it was diseussed whether these faetors are of importance in elieiting and perpetuating tissue infiltration by neutrophils. Eurthermore, there was some evidenee that epidermal eells are able to produee ehemotaetie lipids sueh as LTB4 (6, 7) and 12-HETE (8) and therefore these faetors appeared to explain the accumulation of neutrophils in psoriatie lesions. Recent studies (9, 10), however, revealed that keratinoeytes apparently produee LTB4 only in very low amounts - if any - and therefore seem not to be the major souree of this potent ehemotaetie faetor. Instead, it is hkely that immigrated neutrophils


produee the majority of LTB4 in the psoriatie lesion. When looking for meehanisms of preferential neutrophil accumulation in the epidermis of aetive psoriasis, another aspect is of great importance: the ehemotaetie faetors mentioned above and deteeted in psoriatic lesions are ehemotaetie for a wide variety of leukocytes and do not show a speeifieity for neutrophils. Therefore it would be diffieult to explain seleetive neutrophil and T lymphoeyte, but not tnonoeyte and eosinophil aeeumulation in the lesional epidermis of aetive psoriasis. Consequently, it was tempting to speeulate whether, apart from the pan-leukoeyte ehemotaetie faetors C5a, LTB4 and PAF, also neutrophil-seleetive attraetants are present in psoriatie epidermis. Identification of neutrophil-selcctivc chemotaxins in psoriatic scales In a re-investigation of neutrophil ehemotaetie aetivity in extracts of psoriatie seale material, apart from lipid-like chemotaxins and C5a,|^.,,g large amounts of an additional proteinaceous neutrophil attraetant termed 'V/nionic //eutrophil activating /;eptide, ANAP" eould be deteeted (11). Sinee ANAP shows a similar moleeular mass as seen for C5a, it may have been overlooked in very early investigations. ANAP is identical to an interlcukin1-like neutrophil ehemotaetie faetor deteeted at the same time (12). Originally, it was suggested that ANAP is structurally identieal to the epidermal eell-derived thymocyte aetivating faetor, ETAF, sinee ETAF preparations have been reported to be chemotactieally active for neutrophils and monocytes (13). With the availability of recombinant IL-1 it was shown that this cytokine exerts no chemotactic activity for neulrophils /// vitro (14). Therefore ANAP cannot be identical to ETAF, the epidermal IL-1. Further evidence for the presence

Chemotaetie cytokines in the epidermis

of another neutrophil chetnotactic cytokine was obtained frotn a size-exclusion HPLCT separation of partially purified ANAP: both activities could be separated from each other (15). When partially purified (C5ajes;,rg-depleted) preparations of ANAP were investigated for chetnotactic activity for neutiophils, monocytes, lymphocytes and eosinophils, chemotaetie activity was seen for neutrophils, but not for other leukocytes (16). ANAP therefore appeared to fulfil the criterion of a neutrophil specificity postulated for attractants responsible for neutrophil infiltration into the psoriatie epidermis, ANAP binds to a separate receptor on neutrophils distinct from those for C5a, EMLP or lipidlike chcmotaxins (II). This has been pi oven by cross-desensitization experiments of PMN-enzyme release using well-defined PMN chemotaetie factors as well as supernatants of bacterial lipopolysaccharide-stimulated blood tnonocytes (11), now known to contain a novel chemotaetie cytokine originally termed MONAP (17), MDNCE (18), NAF (19) and GCP (20) and now NAP-1 /Interleukin 8 (21), Therefore it appeared to be likely that psoriasis-derived ANAP is structurally similar or identical to IL-8. In recent investigations the molecular nature of ANAP was determined by the use of HPLC technology. As a result it became clear that ANAP is heterogenous, consisting of at least nine biochemically different PMN chemotaetie cytokines (15), which all show cross-desensitization with IL-8 in a PMN enzyme release assay, indicating binding to lhe IL-8 receptors which recently were cloned (22, 23). Purification and subsequent aniinoterminal amino acid sequence characterization of the major ANAP forms revealed identity with the 69-residue form of lL-8 (P.-ANAP) and another structurally related molecule (24) termed "melanoma growth stimulatory activity, MGSA" (25), which is identical lo the gene product of lhe oncogene "gro" (26). The third and tninor PMN chemotaetie cytokine is identical with the biologically fully-active 72-residuc form of IL-8 (24). Olher minor neutrophil chemotaclic cytokines present in psoriatie scale material may represent processed forms of either IL-8 or MGSA/gro: when we analyzed purified low M, chetnotactic cytokines, two compounds revealed identical aminoterminal amino acid sequences as found

Chemotactic cytokines in the epidermis.

Chemotactic cytokines in the epidemiis Schroder J-M. Chemotactic cytokines in the epidermis. Exp Dermatol 1992: 1: 12-19. Jens-Michael Schroder Depat...
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