Corticotropin is produced by keratinocytes and may have an immunoregulatory role in oral mucosa and skin. We have investigated its effects on a human oral keratinocyte cell line and shown that corticotropin, acting via its specific receptor, stimulates a dose-dependent increase in DNA synthesis and induces cell proliferation. When cells were incubated in the presence of increasing concentrations of corticotropin, there were significant increases in intracellular cAMP levels. Corticotropin-stimulated mitogenesis and cell proliferation were attenuated by the adenylyl cyclase inhibitor SQ22,536, but were unaffected by inhibitors of protein kinase C or tyrosine kinase. These data identify corticotropin as a mitogenic regulatory peptide of keratinocytes acting via cAMP.Keywords : corticotropin; cAMP ; keratinocyte ; mitogenesis; proliferation.Corticotropin is a well characterised peptide hormone secreted by the pituitary gland which upregulates synthesis of adrenocorticosteroids through activation of adenylyl cyclase and increases in cAMP [1] and plays a key role in the response of the body to stress. The immune system is also affected by stress and there is some evidence that corticotropin may have an immunomodulatory function. It reduces immunoglobulin production by B lymphocytes and increases their growth and differentiation [2,3]. These effects are believed to be mediated via specific corticotropin receptors which are found on the lymphocyte cell surface as determined by radioligand-binding assay [4,5].It has recently become apparent that production of corticotropin is not restricted to the pituitary. Among other cell types, it is synthesised and released by human keratinocytes in response to a number of stimuli including phorbol myristate acetate, ultraviolet light and interleukin-1 [6,7]. Since keratinocytes play an important role in the regulation of the immune response in the skin and oral mucosa by releasing proinflamatory cytokines [8], these findings raise the possibility that corticotropin may also have an immunoregulatory function. However the target cell for its action is unknown. The aims of this study were threefold; to determine firstly whether corticotropin receptors are present on human oral keratinocytes, secondly the nature of the signalling system and thirdly whether corticotropin affects keratinocyte function in terms of cell proliferation.This study reports that the human oral keratinocytes, H357, express receptors of specific high affinity for corticotropin and show that corticotropin causes an increase in cAMP accumulation and induces mitogenesis and stimulates cell proliferation. Furthermore these effects are mimicked by the cell permeable cAMP analogue, dibutyryl cAMP (Bt2-cAMP). Corticotropinstimulated mitogenesis of H357 cells was abolished in the presence of SQ22,536, a specific antagonist of adenylyl cyclase. Inhibitors of protein kinase C (PKC) or tyrosine kinase were without effect on corticotropin-stimulated mitogenic events. These results identify corticotropin working directly as ...