C-Cbl-associated protein (CAP), also known as Sorbin and SH3 domain-containing protein 1 (Sorbs1) or ponsin, an adaptor protein of the insulin-signalling pathway, mediates anti-viral and anti-cytotoxic protection in acute viral heart disease. In the present study we describe a novel protective immuno-modulatory function of CAP in inflammation.

Among the three members of the Sorbs family of adapter molecules, which include CAP (Sorbs1), ArgBP2 (Sorbs2), and Vinexin (Sorbs3), CAP consistently down-regulated the expression of pro-inflammatory cytokines in mouse fibroblasts, cardiomyocytes, and myeloid-derived leukocytes, after Toll-like receptor (TLR) stimulation. Upon the same TLR stimulation, ArgBP2 partially down-regulated pro-inflammatory cytokine production in mouse fibroblasts and cardiomyocytes, while Vinexin rather promoted their production. Mechanistically, CAP limited pro-inflammatory cytokine expression by suppressing the phosphorylation of Inhibitor of kappa B (IκB) kinase (Iκκ)-α and Iκκ-β and their downstream NF-κB-dependent signalling pathway. Molecular affinity between CAP and Iκκ-α/ Iκκ-β was necessary to block the NF-κB pathway. The CAP-dependent inhibitory mechanism - in vivo exclusively IL-6 inhibition - was confirmed after collecting blood from mice with systemic inflammation induced by lipopolysaccharide (LPS) and in the heart tissue collected from mice infected with the cardiotropic Coxsackievirus B3 (CVB3).

Taken together, CAP down-regulates pro-inflammatory cytokines by interfering with the normal function of the NF-κB pathway. The promotion of CAP production could support the development of new strategies aiming to limit excessive and detrimental activation of the immune system.

C-Cbl相关蛋白（CAP），也称为含Sorbin和SH3结构域的蛋白1（Sorbs1）或ponsin，胰岛素信号通路的衔接蛋白，在急性病毒性心脏中介导抗病毒和抗细胞毒性的保护作用疾病。在本研究中，我们描述了CAP在炎症中的新型保护性免疫调节功能。

在Sorbs衔接子分子的三个成员中，包括CAP（Sorbs1），ArgBP2（Sorbs2）和Vinexin（Sorbs3），CAP始终下调小鼠成纤维细胞，心肌细胞和髓样细胞中促炎细胞因子的表达。 Toll样受体（TLR）刺激后的白细胞。在相同的TLR刺激下，ArgBP2部分下调了小鼠成纤维细胞和心肌细胞中促炎性细胞因子的产生，而Vinexin则促进了它们的产生。从机理上讲，CAP通过抑制κB（IκB）激酶（Iκκ）-α和Iκκ-β抑制剂及其下游NF-κB依赖性信号通路的磷酸化来限制促炎细胞因子的表达。CAP和Iκκ-α/Iκκ-β之间的分子亲和力是阻断NF-κB通路所必需的。

总之，CAP通过干扰NF-κB途径的正常功能来下调促炎性细胞因子。CAP生产的促进可以支持旨在限制免疫系统过度和有害活化的新策略的开发。