EFFECT OF TRIGGERING EPIDERMAL FC-GAMMA RECEPTORS ON THE INTERLEUKIN-2-INDUCED AND INTERLEUKIN-6-INDUCED UP-REGULATION OF IA-ANTIGEN EXPRESSION BY MURINE EPIDERMAL LANGERHANS CELLS - THE ROLE OF PROSTAGLANDINS AND CAMP

Following incubation of murine epidermis in medium containing either interleukin-2 or interleukin-6, there is significant upregulation in the density of Ia+ epidermal Langerhans cells (to 159% and 175% of control, respectively). This cytokine-induced upregulation is abrogated by either rabbit or human IgG due to triggering of Fc-gamma receptors. In contrast, human IgA does not inhibit the effect of interleukin-2 or interleukin-6. Using different isotypes of murine IgG, we have demonstrated that all subclasses are capable of inhibiting the cytokine-induced enhancement of Ia antigen, although IgG1 and IgG2b must be heat aggregated to be effective. The IgG-mediated events are dependent on prostaglandin synthesis because they can be blocked by the cyclooxygenase inhibitor indomethacin, 10-mu-g/ml. The responsible PG appears to be PGD2; in contrast to its known inhibitory effect on macrophages, PGE2 does not inhibit the upregulation of Ia antigen on Langerhans cells. In addition, these IgG-mediated events are dependent upon the generation of cAMP because they can be blocked by the adenylate cyclase inhibitor 2',5'-dideoxyadenosine, 1 mM. Despite the apparently central role of PGD2 and cAMP in this process, triggering of the Fc-gamma-R by different isotypes of IgG blocks upregulation of Ia via at least two different pathways. The inhibition caused by aggregated IgG1 or IgG2b, which bind to Fc-gamma-RII on Langerhans cells, is abrogated by para-bromophenacylbromide, an inhibitor of phospholipase A2. In contrast, the inhibition caused by monomeric IgG2a, which binds to Fc-gamma-RI most likely on keratinocytes, or monomeric IgG3, which probably binds to this same Fc-gamma-RI, is abrogated by staurosporine, an inhibitor of protein kinase C, as well as by W7, a calmodulin antagonist. Finally, 1,2 dioctanoyl-rac-glycerol, an activator of protein kinase C, mimics the Ig-mediated events. Based on these findings, as well as studies using monoclonal antibodies to the murine Fc-gamma receptors I and II, we conclude that, as is the case in murine macrophages, triggering of an epidermal Fc-gamma-RI, most likely on keratinocytes, results in the generation of cAMP via a Ca++-dependent protein kinase C pathway, whereas triggering of an epidermal Fc-gamma-RII, most likely on Langerhans cells, results in the elevation of cAMP via a phospholipase A2-mediated pathway. In contrast to the situation for macrophages, PGD2 is a vital intermediate in both pathways, perhaps because Langerhans cells have receptors for only this prostaglandin. Triggering of the receptor for PGD2 on Langerhans cells induces the elevation of intracellular cAMP, which appears to act as the final messenger abrogating the cytokine-induced upregulation of Ia antigen on this cell.