SIGIRR Inhibits Interleukin-1 Receptor- and Toll-like Receptor 4-mediated Signaling through Different Mechanisms

Abstract

The Toll-interleukin-1 receptor (TIR) 1 superfamily, a large family of proteins defined by the presence of an intracellular TIR domain, plays crucial roles in the immune response. This superfamily can be divided into two main subgroups, based on the extracellular domains: the immunoglobulin (Ig) domaincontaining receptors (1), and the leucine-rich repeat motifcontaining receptors (2). The Ig domain subgroup includes IL-1R1, IL-18 receptor, T1/ST2, and SIGIRR. IL-1 has been demonstrated to be a key player in the immune response and inflammatory response at both local and systemic levels by activating gene expression of such genes as MIP-2, KC, and C-reactive protein. IL-18 plays important roles in promoting Th1 cell differentiation and natural killer cell activation. T1/ ST2 (3) and SIGIRR (4), also known as TIR8 (5), have been shown to function as negative regulators for Toll-IL-1R-mediated signaling. The leucine-rich repeat motif subgroup consists of at least 11 Toll-like receptors (TLRs) (2, 6 -10). These receptors have received intense attention because different TLRs were found to be activated by specific pathogen products (8,(11)(12)(13)(14)(15)(16).Due to the similarity in their intracellular domain, the Toll-IL-1 receptors employ related yet distinct signaling components and downstream pathways. Genetic and biochemical studies revealed that IL-1R mediates a very complex pathway involving a cascade of kinases organized by multiple adapter molecules into signaling complexes, leading to activation of the transcription factors NF-B, ATF, and AP-1 (17-19). Based on published studies (20 -23), a model of the IL-1 pathway is postulated. Upon IL-1 stimulation, adapter molecule MyD88 (24) is first recruited to the IL-1 receptor, followed by the recruitment of two serine-threonine kinases, IRAK4 (25,26) and IRAK (27,28), and the adapter TRAF6 (29), resulting in the formation of the receptor complex (Complex I). During the formation of Complex I, IRAK and IRAK4 are activated, leading to the hyperphosphorylation of IRAK. Pellino 1⅐IRAK4⅐IRAK⅐TRAF6 complex is then formed, releasing these signaling molecules from the receptor (20). The released components interact with the membrane bound pre-associated TAK1⅐TAB1⅐TAB2⅐TAB3 (21, 23), resulting in the formation of Complex II (IRAK⅐TRAF6⅐TAK1⅐TAB1⅐TAB2⅐TAB3), followed by the translocation of TRAF6⅐TAK1⅐TAB1⅐TAB2⅐TAB3 (Complex III) from the membrane to the cytosol. The translocated Complex III interacts with additional factors in the cytosol, leading to TAK1 activation. It has been implicated that TRAF6 functions as part of a unique E3 complex, mediating TAK1 activation through nonclassical ubiquitination catalyzed by the ubiquitination proteins Ubc13 and Uev1A (30, 31). Once activated, TAK1 can directly phosphorylate IKK␤ and mitogenactivated protein kinase kinase 6, leading to the activation of both the JNK and NF-B signaling pathways (32-35). In addition to TAK1, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 and 3 have also been i...

SIGIRR modulates the inflammatory response in the brain

“…SIGIRR has been identified as a negative regulator of TLR-mediated innate-immunity in several peripheral cells Garlanda et al, 2004;Qin et al, 2005b;Wald et al, 2003). As LPS is widely known to induce a potent and robust neuroinflammatory response, we hypothesized that it would exert a greater effect in cells prepared from SIGIRR -/-, compared with wildtype mice.…”

“…To assess this, the responses of mixed glial cells prepared from SIGIRR -/-and wildtype mice to LPS were compared in terms of cell surface markers of microglial activation and proinflammatory cytokine production. SIGIRR negatively regulates TLR-mediated signalling through inhibition of IRAK and TRAF-6 (Qin et al, 2005b;Wald et al, 2003). Therefore, we chose to evaluate CD40 since CD40-mediated signaling requires recruitment of TRAF-6 (Ishida et al, 1996).…”

“…SIGIRR is unable to bind IL-1α, IL-1β or IL-1ra (Thomassen et al, 1999) but it can interact with IRAK and TRAF-6, which likely infers its ability to inhibit TLR/IL-1-induced signalling (Qin et al, 2005b;Wald et al, 2003). Its inability to respond to IL-1R-triggered signalling stems from the fact that it lacks two essential amino acids in its highly-conserved TIR domain; therefore cells in which various SIGIRR constructs were expressed failed to exhibit evidence of NFκB activation (Polentarutti et al, 2003;Thomassen et al, 1999).…”

“…Similarly, kidney cells and tubular epithelial cells (Lech et al, 2007;Qin et al, 2005b), splenocytes (Wald et al, 2003), bone-derived macrophages and dendritic cells Garlanda et al, 2004) prepared from SIGIRR -/-mice respond more robustly to LPS and/or IL-1 than cells prepared from wildtype mice, generally assessed in terms of production of chemokines and inflammatory cytokines. Further evidence of the antiinflammatory influence of SIGIRR has been obtained from studies in which the receptor was overexpressed; for example, Huang and colleagues demonstrated that RAW cells transfected with SIGIRR resulted in a decreased production of inflammatory cytokines, IL-1β, IL-12, IL-18 and IFN-γ (Huang et al, 2006).…”

“…Further evidence of the antiinflammatory influence of SIGIRR has been obtained from studies in which the receptor was overexpressed; for example, Huang and colleagues demonstrated that RAW cells transfected with SIGIRR resulted in a decreased production of inflammatory cytokines, IL-1β, IL-12, IL-18 and IFN-γ (Huang et al, 2006). In addition to a role of SIGIRR in attenuating Toll-like receptor (TLR)4 and IL-IRI signalling, the evidence suggests that SIGIRR also attenuates inflammatory changes induced by activation of TLR1, TLR3 and TLR9 by lipopeptide (Pam3Cys), polyinosinic:polycytidylic acid (Poly I:C) and CpG-DNA, respectively (Garlanda et al, 2004;Lech et al, 2007;Qin et al, 2005b;Wald et al, 2003;Xiao et al, 2007).…”