Cytokines of the interleukin-1 (IL-1) family, such as IL-1 alpha/beta and IL-18, have important functions in host defense, immune regulation, and inflammation. Insight into their biological functions has led to novel therapeutic approaches to treat human inflammatory diseases. Within the IL-1 family, IL-1 alpha/beta, IL-1Ra, and IL-18 have been matched to their respective receptor complexes and have been shown to have distinct biological functions. The most prominent orphan IL-1 receptor is ST 2. This receptor has been described as a negative regulator of Toll-like receptor-IL-1 receptor signaling, but it also functions as an important effector molecule of T helper type 2 responses. We report a member of the IL-1 family, IL-33, which mediates its biological effects via IL-1 receptor ST 2, activates NF-kappaB and MAP kinases, and drives production of T(H)2-associated cytokines from in vitro polarized T(H)2 cells. In vivo, IL-33 induces the expression of IL-4, IL-5, and IL-13 and leads to severe pathological changes in mucosal organs.

The Toll-like receptor-interleukin 1 receptor signaling (TLR-IL-1R) receptor superfamily is important in differentially recognizing pathogen products and eliciting appropriate immune responses. These receptors alter gene expression, mainly through the activation of nuclear factor-kappaB and activating protein 1. SIGIRR (single immunoglobulin IL-1R-related molecule), a member of this family that does not activate these factors, instead negatively modulates immune responses. Inflammation is enhanced in SIGIRR-deficient mice, as shown by their enhanced chemokine induction after IL-1 injection and reduced threshold for lethal endotoxin challenge. Cells from SIGIRR-deficient mice showed enhanced activation in response to either IL-1 or certain Toll ligands. Finally, biochemical analysis indicated that SIGIRR binds to the TLR-IL-1R signaling components in a ligand-dependent way. Our data show that SIGIRR functions as a biologically important modulator of TLR-IL-1R signaling.

Despite constant contact with the large population of commensal bacteria, the colonic mucosa is normally hyporesponsive to these potentially proinflammatory signals. Here we report that the single immunoglobulin IL-1 receptor-related molecule (SIGIRR), a negative regulator for Toll-IL-1R signaling, plays a critical role in gut homeostasis, intestinal inflammation, and colitis-associated tumorigenesis by maintaining the microbial tolerance of the colonic epithelium. SIGIRR-deficient (Sigirr(-/-)) colonic epithelial cells displayed commensal bacteria-dependent homeostatic defects, as shown by constitutive upregulation of inflammatory genes, increased inflammatory responses to dextran sulfate sodium (DSS) challenge, and increased Azoxymethane (AOM)+DSS-induced colitis-associated tumorigenesis. Gut epithelium-specific expression of the SIGIRR transgene in the SIGIRR-deficient background reduced the cell survival of the SIGIRR-deficient colon epithelium, abrogated the hypersensitivity of the Sigirr(-/-) mice to DSS-induced colitis, and reduced AOM+DSS-induced tumorigenesis. Taken together, our results indicate that epithelium-derived SIGIRR is critical in controlling the homeostasis and innate immune responses of the colon to enteric microflora.

SUMMARY L3mbtl2 has been implicated in transcriptional repression and chromatin compaction but its biological function has not been defined. Here we show that disruption of L3mbtl2 results in embryonic lethality with failure of gastrulation. This correlates with compromised proliferation and abnormal differentiation of L3mbtl2−/− embryonic stem (ES) cells. L3mbtl2 regulates genes by recruiting a Polycomb Repressive Complex1 (PRC1)-related complex, resembling the previously described E2F6-complex, and including G9A, Hdac1, and Ring1b. Presence of L3mbtl2 at target genes is associated with H3K9-dimethylation, low histone-acetylation, and H2AK119-ubiquitination, but the latter is neither dependent on L3mbtl2 nor sufficient for repression. Genome wide studies revealed that the L3mbtl2-dependent complex predominantly regulates genes not bound by canonical PRC1 and PRC2. However, some developmental regulators are repressed by the combined activity of all three complexes. Together, we have uncovered a highly selective, essential role for an atypical PRC1-family complex in ES cells and early development.

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...

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TNF receptor (TNFR) superfamily members, CD40, and BAFFR play critical roles in B cell survival and differentiation. Genetic deficiency in a novel adaptor molecule, Act1, for CD40 and BAFF results in a dramatic increase in peripheral B cells, which culminates in lymphadenopathy and splenomegaly, hypergammaglobulinemia, and autoantibodies. While the B cell-specific Act1 knockout mice displayed a similar phenotype with less severity, the pathology of the Act1-deficient mice was mostly blocked in CD40-Act1 and BAFF-Act1 double knockout mice. CD40- and BAFF-mediated survival is significantly increased in Act1-deficent B cells, with stronger IkappaB phosphorylation, processing of NF-kappaB2 (p100/p52), and activation of JNK, ERK, and p38 pathways, indicating that Act1 negatively regulates CD40- and BAFF-mediated signaling events. These findings demonstrate that Act1 plays an important role in the homeostasis of B cells by attenuating CD40 and BAFFR signaling.

A novel cytokine IL-33, an IL-1 family member, signals via ST2 receptor and promotes Th2 responses, through the activation of NF-κB and MAP kinases. Previous studies reported that single Ig IL-1R-related molecule (SIGIRR)/Toll IL-1R8 acts as negative regulator for TLR-IL-1R-mediated signaling. We now found that SIGIRR formed a complex with ST2 upon IL-33 stimulation and specifically inhibited IL-33/ST2-mediated signaling in cell culture model. Furthermore, IL-33-induced Th2 response was enhanced in SIGIRR-deficient mice compared with that in wild-type control mice, suggesting a negative regulatory role of SIGIRR in IL-33/ST2 signaling in vivo. Similar to ST2, SIGIRR was highly expressed in in vitro polarized Th2 cells, but not Th1 cells. SIGIRR-deficient Th2 cells produce higher levels of Th2 cytokines, including IL-5, IL-4, and IL-13, than that in wild-type cells. Moreover, SIGIRR-deficient mice developed stronger Th2 immune response in OVA-challenged asthma model. Taken together, our results suggest that SIGIRR plays an important role in the regulation of Th2 response in vivo, possibly through its impact on IL-33-ST2-mediated signaling.