Swope V B, Abdel-Malek Z, Kassem L M, Nordlund J J
Department of Dermatology, University of Cincinnati College of Medicine, Ohio 45267-0592.
J Invest Dermatol. 1991 Feb;96(2):180-5. doi: 10.1111/1523-1747.ep12460991.
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 3H-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 3H-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.
白细胞介素（IL）-1α、IL-6和肿瘤坏死因子（TNF）-α是产生许多相似生物学效应的表皮细胞因子。我们研究了这些细胞因子作为培养的正常人黑素细胞（NHM）黑素生成和增殖调节因子的可能性。在处理48小时后，所有这三种细胞因子均引起酪氨酸酶活性呈剂量依赖性降低。IL-1α具有最大的抑制作用，在浓度为3×10⁻¹⁴ M时导致酪氨酸酶活性受到22%的抑制。4×10⁻¹¹ M的IL-6和10⁻¹¹ M的TNF-α产生了同等效果。通过³H-胸苷掺入率降低和倍增时间增加来衡量，所有这三种细胞因子也抑制黑素细胞增殖。6×10⁻¹⁴ M、6×10⁻¹³ M和3×10⁻¹² M的IL-1α、10⁻¹⁰ M、10⁻⁹ M和10⁻⁸ M的TNF-α以及4×10⁻¹⁰和1.2×10⁻⁹ M的IL-6产生了³H-胸苷掺入的剂量依赖性抑制。IL-1α、TNF-α和IL-6的作用是细胞生长抑制性的，而非细胞毒性的，因为在多次用这些细胞因子处理后黑素细胞仍保持存活。此外，用IL-1α和TNF-α处理的黑素细胞在停止处理后恢复并重新开始增殖。IL-1α、IL-6和TNF-α的这些作用似乎不是由类花生酸生成的刺激介导的，因为环氧化酶抑制剂吲哚美辛和脂氧合酶抑制剂去甲二氢愈创木酸对花生四烯酸（AA）代谢的抑制并未逆转对NHM增殖或酪氨酸酶活性的抑制作用。这是首次证明NHM对表皮细胞因子有反应，并提示免疫调节剂对黑素细胞的旁分泌以及可能的自分泌调节作用。
