Regulation and role of interleukin 6 in wounded human epithelial keratinocytes

Dermal wounding is accompanied by inflammation and the resulting proinflamm atory cytokines, including interleukin (IL)-6, are thought to play an impor tant role in the repair process. IL-6 is produced by normal human keratinoc ytes to various dermatological diseases and we have recently shown it is al so required for normal wound repair. However, neither the events responsibl e for its induction nor its role in repair have been clearly identified. Us ing a recently developed in vitro wounding model, we demonstrate that IL-6 mRNA is expressed and immunoreactive IL-6 is released from cultures of huma n epidermal keratinocytes (NHEKs) following wounding. The transcription fac tors, NF kappaB and NF-IL-6 (C/EBP beta), which coordinately help regulate IL-6 expression, were activated following wounding and preceded the appeara nce of IL-6. Addition of IL-1 alpha to NHEK cultures increased IL-6 product ion and activated NF kappaB and C/EBP beta. Addition of the IL-1 alpha rece ptor antagonist inhibited both IL-6 mRNA expression and the transcription f actors following wounding. Immunoreactive IL-1a was detected in the medium following wounding in the absence of new message. Furthermore, addition of IL-6 to NHEK cultures decreased the expression of keratins 1 and 10, differ entiation markers of keratinocytes, while proliferation was not affected. T aken together, these data indicate that constitutive keratinocyte-derived I L-lu is a stimulus for IL-6 production in wounded epidermis, the response i nvolves NF kappaB and C/EBP beta transcription factors, and IL-6 may be ass ociated with modulation of keratinocyte differentiation rather than prolife ration.