1. Institute of Immunology, University of Kiel, Michaelisstr. 5, 24105 Kiel, Germany
2. ^*Department of Dermatology, University of Kiel, Schittenhelmstr. 7, 24105 Kiel, Germany
3. ^†Legekontoret i Bussedalen, 3616 Kongsberg, Norway

Correspondence: Prof Dr med. Enno Christophers, Department of Dermatology, University of Kiel, Schittenhelmstr. 7, 24105 Kiel, Germany. Email: echristophers@dermatology.uni-kiel.de

Received 18 July 2001; Revised 16 July 2002; Accepted 25 July 2002.

Abstract

The CXC chemokines, interleukin-8 and growth-related oncogene, are known to play a prominent part in wound healing as well as inflammatory skin disorders, including psoriasis. Both chemokines are potent neutrophil activators and were discussed as potential stimuli in keratinocyte growth. We examined the action of growth-related oncogene and interleukin-8 in organotypic raft culture, which resembles in vivo skin in several respects. Addition of growth-related oncogene and interleukin-8 resulted in a time- and concentration-dependent epidermal hyperproliferation in organotypic cultures. In cryostat sections an increased number of epidermal layers as well as significantly elevated number of Ki-67-stained keratinocytes indicate marked hyperproliferation with no evidence for the reduction of apoptotic cells. Terminal differentiation was shown to proceed in a regular fashion with formation of a cornified layer and the expression of suprabasal keratins in addition to the presence of differentiation markers. Interleukin-8-mediated hyperproliferation was inhibited by a blocking human monoclonal antibody. To demonstrate a specific receptor-mediated action of growth-related oncogene and interleukin-8, we used a CXC receptor 2 monoclonal antibody or a CXC receptor 2 selective nonpeptide antagonist, both of which lead to inhibition of interleukin-8-mediated hyperproliferation. Interleukin-1 caused induction of interleukin-8 and growth-related oncogene mRNA as well as marked epidermal hyperproliferation. The interleukin-1-mediated hyperproliferation was markedly reduced by both the interleukin-8-specific antibody and the CXC receptor 2 antagonist, indicating close correlation between the interleukin-8/CXC receptor 2 pathway and interleukin-1-induced keratinocyte growth stimulation. Our data indicate that interleukin-1 induces overexpression of interleukin-8 and growth-related oncogene in human keratinocytes. These changes correlate with characteristic functional alterations of the epidermis as observed in psoriasis and wound healing.