INTERLEUKIN-1-ALPHA AND INTERLEUKIN-6 AND TUMOR-NECROSIS-FACTOR-ALPHA ARE PARACRINE INHIBITORS OF HUMAN MELANOCYTE PROLIFERATION AND MELANOGENESIS

Interleukin (IL)-1-alpha, IL-6, and tumor necrosis factor (TNF)-alpha are epidermal cytokines that produce many similar biologic effects. We have investigated the possibility that these cytokines act as regulators of melanization and proliferation of cultured normal human melanocytes (NHM). All three cytokines elicited a dose-dependent decrease in the activity of the enzyme tyrosinase after 48 h of treatment. IL-1-alpha had the greatest inhibitory effect, resulting in a 22% inhibition of tyrosinase activity at a concentration of 3 X 10(-14) M. An equivalent effect was elicited by 4 X 10(-11) M IL-6 and 10(-11) M TNF-alpha. All three cytokines also inhibited melanocyte proliferation, as measured by a decrease in the rate of H-3-thymidine incorporation and an increase in doubling time. IL-1-alpha at 6 X 10(-14) M, 6 X 10(-13) M, and 3 X 10(-12) M, TNF-alpha at 10(-10) M, 10(-9) M, and 10(-8) M, and IL-6 at 4 X 10(-10) and 1.2 X 10(-9) M produced a dose-dependent inhibition of H-3-thymidine incorporation. The effects of IL-1-alpha, TNF-alpha, and IL-6 were cytostatic, not cytotoxic, because melanocytes remained viable following several treatments with the cytokines. Also, melanocytes treated with IL-1-alpha and TNF-alpha recovered and resumed proliferation after cessation of treatment. These effects of IL-1-alpha, IL-6, and TNF-alpha do not seem to be mediated by stimulation of eicosanoid production, because inhibition of arachidonic acid (AA) metabolism by indomethacin, a cyclooxygenase inhibitor, and nordihydroguaiaretic acid, a lipoxygenase inhibitor, did not reverse the inhibitory effects on either proliferation or tyrosinase activity of NHM. This is the first demonstration that NHM respond to epidermal cytokines, and suggests a role for paracrine and possibly autocrine regulation of melanocytes by immune modulators.