Raf Kinase Inhibitor Protein Preferentially Promotes TLR3-Triggered Signaling and Inflammation

Abstract

Raf kinase inhibitor protein (RKIP) protects against host immunological responses in nematodes and Whether RKIP functions in innate immune responses in mammals remains unknown. In this article, we report that RKIP preferentially regulates the TLR3-mediated immune response in macrophages. RKIP deficiency or silencing significantly decreases polyinosinic:polycytidylic acid [Poly(I:C)]-induced IFN-β, IL-6, and TNF-α production without affecting the counterpart induced by LPS or CpG. Compared with their wild-type counterparts, RKIP-deficient mice produce less IFN-β, IL-6, and TNF-α in serum and display decreased lethality upon peritoneal Poly(I:C) plus d-galactosamine injection. Mechanistically, RKIP interacts with TBK1 and promotes the Poly(I:C)-induced TANK-binding kinase 1/IRF3 activation. Simultaneously, RKIP enhances the Poly(I:C)-induced interaction between TGF-β-activated kinase 1 and MAPK kinase 3 (MKK3), thus promoting MKK3/6 and p38 activation. We further demonstrated that Poly(I:C) treatment, but not LPS treatment, induces RKIP phosphorylation at S109. This action is required for RKIP to promote TANK-binding kinase 1 activation, as well as the interaction between TGF-β-activated kinase 1 and MKK3, which lead to activation of the downstream IRF3 and p38, respectively. Therefore, RKIP acts as a positive-feedback regulator of the TLR3-induced inflammatory response and may be a potential therapeutic target for inflammatory disease.

Elevated microRNA-129-5p level ameliorates neuroinflammation and blood-spinal cord barrier damage after ischemia-reperfusion by inhibiting HMGB1 and the TLR3-cytokine pathway

“…TLR3 is a unique member of the TLR family that is located in endosomal compartments or on the cell surface [ 27 ]. TLR3 usually recognizes pathogen-derived nucleic acids and recruits an adaptor protein to induce interferon-ß release [ 17 , 28 ]. Recently, several studies investigated the essential roles of TLR3 activation in the amplification of inflammatory responses and cytokine release in response to HMGB1 [ 17 , 29 , 30 ].…”

Raf kinase inhibitor protein negatively regulates FcεRI-mediated mast cell activation and allergic response

“…RKIP is well established as an inhibitory molecule in oncological processes (14). We recently demonstrated that RKIP is involved in colitis and antiviral innate immune responses, indicating that RKIP functions as an important mediator in immune response (15)(16)(17). Here, we found that RKIP deficiency in mast cells does not affect the development of mast cells or the expression of surface markers, including FceRI and c-Kit, but significantly inhibits the IgE−FceRI-mediated early-phase mediators, including histamine and β-hexosaminidase, and late-phase mediators, such as type 2 cytokines, proinflammatory cytokines, and other related chemokines (CCL1, CCL2).…”

“…Collectively, our findings not only suggest that RKIP plays an important role in controlling mast cell-mediated allergic responses but also provide insight into therapeutic targets for mast cell-related allergic diseases. (17). Therefore, RKIP functions as a physiological and pathological regulator more than as a tumor suppressor.…”

RKIP as an Inflammatory and Immune System Modulator: Implications in Cancer

“…In addition, RKIP-deficient mice produced fewer pro-inflammatory cytokines and type I interferons and were more resistant to Poly(I:C)-induced death. It was further demonstrated that Poly(I:C) treatment induces RKIP phosphorylation at S109, being this action required for RKIP to promote TLR3-mediated signalling and inflammation [62].…”