Center for Translational Medicine, State Key Laboratory of Analytical Chemistry for Life Science & Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, 210093, People's Republic of China.
Department of Dermatology, Drum Tower Hospital, Medical School, Nanjing University, Nanjing, 210008, China.
J Mol Med (Berl). 2021 Jul;99(7):1009-1020. doi: 10.1007/s00109-021-02073-3. Epub 2021 Apr 9.
IL-6 has been suggested to function as an autocrine mitogen in the psoriatic epidermis. The biological activity of IL-6 relies on interactions with its receptors, including the membrane-bound IL-6 receptor (mIL-6R) and soluble IL-6 receptor (sIL-6R). Our study presents data showing that the levels of plasma IL-6 and sIL-6R were elevated in psoriatic patients. Genotyping of two single-nucleotide polymorphisms (SNPs) in IL-6R (rs4845617 and rs2228145) demonstrated that the SNP IL-6R (rs4845617) rather than IL-6R (rs2228145) shows a significant association with psoriasis (P = 0.006). To verify the functions of sIL-6R, cultured keratinocytes and imiquimod (IMQ)-induced psoriatic model mice were treated with sIL-6R. We found that the presence of sIL-6R in the HaCaT cell culture medium enhanced the IL-6-induced Stat3 activation, which resulted in abnormal keratinocyte proliferation and aberrant differentiation. Furthermore, the application of sIL-6R in vivo accelerated the pathological development of the disease. Our results demonstrate for the first time that genetic polymorphisms in the IL-6R gene are associated with psoriasis disease phenotypes in a Chinese psoriatic patient population; sIL-6R-mediated trans-signaling pathway plays a pivotal role in keratinocyte proliferation and differentiation, suggesting potential therapeutics for psoriasis. KEY MESSAGES: Patients with psoriasis displayed higher levels of IL-6 and sIL-6R compared with healthy controls. Analysis of genotypes revealed that IL-6R rs4845617 GG genotype associated with the risk of psoriasis. Supplement of sIL-6R further enhanced IL-6-induced Stat3 activation in keratinocytes. In vivo administration of sIL-6R accelerated, whereas sgp130FC alleviated, the pathological development of psoriasis.
白细胞介素 6（IL-6）被认为在银屑病表皮中作为自分泌有丝分裂原发挥作用。IL-6 的生物学活性依赖于与其受体的相互作用，包括膜结合白细胞介素 6 受体（mIL-6R）和可溶性白细胞介素 6 受体（sIL-6R）。我们的研究提供的数据显示，银屑病患者的血浆 IL-6 和 sIL-6R 水平升高。IL-6R 中的两个单核苷酸多态性（SNP）（rs4845617 和 rs2228145）的基因分型表明，SNP IL-6R（rs4845617）而不是 IL-6R（rs2228145）与银屑病显著相关（P=0.006）。为了验证 sIL-6R 的功能，用 sIL-6R 处理培养的角质形成细胞和咪喹莫特（IMQ）诱导的银屑病模型小鼠。我们发现，HaCaT 细胞培养物中 sIL-6R 的存在增强了 IL-6 诱导的 Stat3 激活，导致角质形成细胞异常增殖和异常分化。此外，sIL-6R 在体内的应用加速了疾病的病理发展。我们的研究结果首次证明，IL-6R 基因的遗传多态性与中国银屑病患者群体的银屑病疾病表型相关；sIL-6R 介导的转信号通路在角质形成细胞增殖和分化中起关键作用，为银屑病提供了潜在的治疗方法。
与健康对照组相比，银屑病患者的 IL-6 和 sIL-6R 水平更高。基因型分析显示，IL-6R rs4845617 GG 基因型与银屑病的发病风险相关。sIL-6R 的补充进一步增强了角质形成细胞中 IL-6 诱导的 Stat3 激活。体内给予 sIL-6R 加速了银屑病的病理性发展，而 sgp130FC 则缓解了银屑病的病理性发展。
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