International Immunology, Vol. 14, No. 6, pp. 669-676,
June 2002
© 2002 Japanese Society for Immunology
CD40 ligation-induced cytokine production in human skin explants is partly mediated via IL-1
1 Department of Immunology, Erasmus University and University Hospital Rotterdam, PO Box 1738,3000 DR Rotterdam, The Netherlands 2 Tanox Pharma BV, Kruislaan 402, 1098 SM Amsterdam, The Netherlands
Correspondence to: J. D. Laman; E-mail: laman{at}immu.fgg.eur.nl
Transmitting editor: W. Knapp
CD40 ligation by CD40 ligand+ CD4+ T cells has been claimed to be involved in inflammatory responses in human skin. However, these data are derived from in vitro cell culture systems and immunohistochemistry, and the mechanisms involved have not been fully elucidated. We previously observed that cells in intact normal human skin secrete high levels of IL-6 and IL-8 upon stimulation with IL-1ß. In vitro studies have shown that CD40 ligation on human keratinocytes results in the production of IL-6 and IL-8 as well. We used a novel tissue culture system with intact normal human skin, and show that antibody ligation of CD40 results in the induction of several pro- and anti-inflammatory cytokines. IL-6, IL-8, tumor necrosis factor (TNF)-
, IL-12 and IL-1ß were induced upon CD40 ligation and IFN-
stimulation, while IL-10 could be induced by CD40 ligation alone and was reduced again by the addition of IFN-. Since CD40 ligation on monocytes and dendritic cells in vitro results in the secretion of IL-1, which is pre-stored in high concentrations in normal human keratinocytes, we subsequently investigated whether CD40 induced IL-6 and IL-8 production in skin is mediated via IL-1. Indeed IL-1 receptor antagonist inhibited the CD40 ligation-induced IL-6 and IL-8 production, while TNF- and IL-10 production were not affected. These data show that CD40 ligation-induced secretion of IL-6 and IL-8, but not TNF- and IL-10, is partially mediated via IL-1 and that IL-1 plays a prominent role in the inflammatory response initiated by CD40 ligation in intact human skin.
Keywords: keratinocytes, IL-1 receptor antagonist, IL-10, inflammation, psoriasis
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