Interleukin-1-stimulated secretion of interleukin-8 and growth-related oncogene-alpha demonstrates greatly enhanced keratinocyte growth in human raft cultured epidermis.

ABSTRACT

The CXC chemokines, interleukin-8 and growth-related oncogenealpha, 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 alpha and interleukin-8 in organotypic raft culture, which resembles in vivo skin in several respects. Addition of growth-related oncogene alpha 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-1alpha caused induction of interleukin-8 and growth-related oncogene alpha mRNA as well as marked epidermal hyperproliferation. The interleukin-1alpha-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 alpha in human keratinocytes. These changes correlate with characteristic functional alterations of the epidermis as observed in psoriasis and wound healing.