Soluble IL-6R-mediated IL-6 trans-signaling activation contributes to the pathological development of psoriasis

Abstract

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.

Keywords: Keratinocyte; Psoriasis; Single-nucleotide polymorphisms; Soluble IL-6 receptor; Stat3.