Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA.
Hum Mol Genet. 2013 May 1;22(9):1807-15. doi: 10.1093/hmg/ddt034. Epub 2013 Jan 31.
The IL12B gene encodes the common p40 subunit of IL-12 and IL-23, cytokines with key roles in Th1 and Th17 biology, respectively, and genetic variation in this region significantly influences risk of psoriasis. Here, we demonstrate that a psoriasis-associated risk haplotype at the IL12B locus leads to increased expression of IL12B by monocytes and correlated with increased serum levels of IL-12, IFN-γ and the IFN-γ induced chemokine, CXCL10. In contrast, serum IL-23 levels were decreased in risk carriers when compared with non-carriers. We further demonstrate that IL-12 is increased in psoriatic skin and that risk carriers manifest a skewing of the inflammatory network toward stronger IFN-γ responses. Taken together, our data demonstrate that the risk variant in IL12B associates with its increased expression and predisposes to stronger Th1 polarization through deviation of the local inflammatory environment toward increased IL-12/IFN-γ at the expense of IL-23/IL-17 responses.
IL12B 基因编码 IL-12 和 IL-23 的共同 p40 亚基，这两种细胞因子分别在 Th1 和 Th17 生物学中起着关键作用，该区域的遗传变异显著影响银屑病的风险。在这里，我们证明了 IL12B 基因座上与银屑病相关的风险单倍型导致单核细胞中 IL12B 的表达增加，并与血清中 IL-12、IFN-γ 和 IFN-γ 诱导的趋化因子 CXCL10 的水平升高相关。相比之下，与非携带者相比，风险携带者的血清 IL-23 水平降低。我们进一步证明，IL-12 在银屑病皮肤中增加，并且风险携带者表现出炎症网络向更强的 IFN-γ 反应倾斜。总之，我们的数据表明，IL12B 中的风险变体与其表达增加相关，并通过向增加的 IL-12/IFN-γ 偏离局部炎症环境，从而导致更强的 Th1 极化，而牺牲 IL-23/IL-17 反应。
