College of Pharmacy, Chungbuk National University, Cheongju 28160, Korea.
College of Pharmacy, Chungnam National University, Daejeon 34134, Korea.
Int J Biol Sci. 2024 Feb 17;20(5):1688-1704. doi: 10.7150/ijbs.93120. eCollection 2024.
Melanocortin 1 receptor (MC1R), a receptor of α-melanocyte-stimulating hormone (α-MSH), is exclusively present in melanocytes where α-MSH/MC1R stimulate melanin pigmentation through microphthalmia-associated transcription factor M (MITF-M). Toll-like receptor 4 (TLR4), a receptor of endotoxin lipopolysaccharide (LPS), is distributed in immune and other cell types including melanocytes where LPS/TLR4 activate transcriptional activity of nuclear factor (NF)-κB to express cytokines in innate immunity. LPS/TLR4 also up-regulate MITF-M-target melanogenic genes in melanocytes. Here, we propose a molecular target of antimelanogenic activity through elucidating inhibitory mechanism on α-MSH-induced melanogenic programs by benzimidazole-2-butanol (BI2B), an inhibitor of LPS/TLR4-activated transcriptional activity of NF-κB. Ultraviolet B (UV-B)-irradiated skins of HRM-2 hairless mice and α-MSH-activated melanocyte cultures were employed to examine melanogenic programs. Topical treatment with BI2B ameliorated UV-B-irradiated skin hyperpigmentation in mice. BI2B suppressed the protein or mRNA levels of melanogenic markers, such as tyrosinase (TYR), MITF-M and proopiomelanocortin (POMC), in UV-B-exposed and pigmented skin tissues. Moreover, BI2B inhibited melanin pigmentation in UV-B-irradiated co-cultures of keratinocyte and melanocyte cells and that in α-MSH-activated melanocyte cultures. Mechanistically, BI2B inhibited the activation of cAMP response element-binding protein (CREB) in α-MSH-induced melanogenic programs and suppressed the expression of MITF-M at the promoter level. As a molecular target, BI2B primarily inhibited mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)-catalyzed kinase activity on p38. Subsequently, BI2B interrupted downstream pathway of p38-mitogen and stress-activated protein kinase-1 (MSK1)-CREB-MITF-M, and suppressed MITF-M-target melanogenic genes, encoding enzymes TYR, TYR-related protein-1 (TRP-1) and dopachrome tautomerase (DCT) in melanin biosynthesis, and encoding proteins PMEL17 and Rab27A in the transfer of pigmented melanosomes to the overlaying keratinocytes in the skin. Targeting the MKK3-p38-MSK1-CREB-MITF-M pathway was suggested as a rationale to inhibit UV-B- or α-MSH-induced facultative melanogenesis and as a strategy to prevent acquired pigmentary disorders in the skin.
黑素皮质素 1 受体（MC1R）是α-黑素细胞刺激素（α-MSH）的受体，仅存在于黑素细胞中，α-MSH/MC1R 通过小眼畸形相关转录因子 M（MITF-M）刺激黑色素生成。Toll 样受体 4（TLR4）是内毒素脂多糖（LPS）的受体，分布于免疫和其他细胞类型中，包括黑素细胞，其中 LPS/TLR4 激活核因子（NF）-κB 的转录活性，以在先天免疫中表达细胞因子。LPS/TLR4 还在上调黑素细胞中 MITF-M 靶标黑素生成基因。在这里，我们通过阐明苯并咪唑-2-丁醇（BI2B）对 LPS/TLR4 激活的 NF-κB 转录活性的抑制机制，提出了抗黑色素生成活性的分子靶标，BI2B 是一种抑制 LPS/TLR4 激活的 NF-κB 转录活性的抑制剂。我们使用 HRM-2 无毛小鼠的紫外线 B（UV-B）照射皮肤和 α-MSH 激活的黑素细胞培养物来检查黑色素生成程序。BI2B 的局部治疗改善了小鼠的 UV-B 照射皮肤色素沉着过度。BI2B 抑制了 UV-B 暴露和色素沉着皮肤组织中黑色素生成标志物的蛋白或 mRNA 水平，如酪氨酸酶（TYR）、MITF-M 和前黑素细胞皮质激素（POMC）。此外，BI2B 抑制了 UV-B 照射的角质形成细胞和黑素细胞共培养物以及 α-MSH 激活的黑素细胞培养物中的黑色素生成。在机制上，BI2B 抑制了 α-MSH 诱导的黑色素生成程序中 cAMP 反应元件结合蛋白（CREB）的激活，并在启动子水平抑制了 MITF-M 的表达。作为一个分子靶标，BI2B 主要抑制丝裂原激活蛋白激酶（MAPK）激酶 3（MKK3）催化的 p38 的激酶活性。随后，BI2B 中断了 p38-MAPK 和应激激活蛋白激酶 1（MSK1）-CREB-MITF-M 的下游途径，并抑制了 MITF-M 靶标黑素生成基因，编码黑色素生物合成中的酶酪氨酸酶（TYR）、酪氨酸相关蛋白-1（TRP-1）和多巴色素互变异构酶（DCT），以及编码在皮肤中向覆盖的角质形成细胞转移色素性黑素体的蛋白 PMEL17 和 Rab27A。靶向 MKK3-p38-MSK1-CREB-MITF-M 途径被认为是抑制 UV-B 或 α-MSH 诱导的兼性黑色素生成的合理策略，并为预防皮肤获得性色素沉着障碍提供了一种策略。
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