SYNTHESIS AND SECRETION OF INTERLEUKIN-1-ALPHA AND INTERLEUKIN-1 RECEPTOR ANTAGONIST DURING DIFFERENTIATION OF CULTURED KERATINOCYTES

Keratinocytes produce interleukin-1 alpha (IL-1 alpha) and the epithel ial variant of its inhibitor, interleukin-1 receptor antagonist (icIL- 1ra). Both IL-1 alpha and icIL-1ra lack a secretory signal peptide; ho wever, some icIL-1ra is found in the supernatants of cultured keratino cytes. The lack of correlation with the release of the cytosolic enzym e lactate dehydrogenase suggests that icIL-1ra can be actively secrete d. Brefeldin A fails to block icIL-1ra release, suggesting that this p rotein may be externalized by keratinocytes through a leaderless pathw ay of secretion. Only minute amounts of soluble extracellular IL-1 alp ha are detected: however, both IL-1 alpha and icIL-1ra can be released from the external face of the keratinocyte plasma membrane by mild ac idic treatment, suggesting that IL-1 alpha can also be secreted by ker atinocytes. The observation of membrane-associated IL-1 alpha and icIL -1ra might reflect an autocrine loop of regulation. Support for this h ypothesis comes from the finding that keratinocytes, when exposed to e xogenous recombinant IL-1 alpha, increase their content in both IL-1 a lpha and IL-1ra mRNA. When keratinocytes are subjected to counterflow centrifugal elutriation, three major cell populations are obtained, re presenting three different degrees of keratinocyte differentiation. Ce lls from all populations synthesize IL-1 alpha and IL-1ra: however, wh ile IL-1 alpha is uniformly distributed in cells from all maturational stages, IL-1ra accumulates in large, more differentiated keratinocyte s. Changes in the ratio of IL-1ra to IL-1 alpha production and secreti on by keratinocytes at different degrees of maturation might contribut e to the control of growth and differentiation of human skin. (C) 1995 Academic Press, Inc.