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The inflammasomes are multiprotein complexes that activate caspase-1 in response to infections and stress, resulting in the secretion of pro-inflammatory cytokines. Here we report that IκB kinase α (IKKα) is a critical negative regulator of apoptosis-associated specklike protein containing a C-terminal caspase-activation-andrecruitment (CARD) domain (ASC)-dependent inflammasomes. IKKα controls the inflammasome at the level of the adaptor ASC, which interacts with IKKα in the nucleus of resting macrophages in an IKKα kinase-dependent manner. Loss of IKKα kinase activity results in inflammasome hyperactivation. Mechanistically, the downstream nuclear effector IKK-related kinase (IKKi) facilitates translocation of ASC from the nucleus to the perinuclear area during inflammasome activation. ASC remains under the control of IKKα in the perinuclear area following translocation of the ASC/IKKα complex. Signal 2 of NLRP3 activation leads to inhibition of IKKα kinase activity through the recruitment of PP2A, allowing ASC to participate in NLRP3 inflammasome assembly. Taken together, these findings reveal a IKKi-IKKα-ASC axis that serves as a common regulatory mechanism for ASC-dependent inflammasomes.

Background & Aims: Commensal bacteria can activate signaling by the Toll-like and interleukin-1 receptors (TLR and IL-1R) to mediate pathogenesis of inflammatory bowel diseases and colitis-associated cancer. We investigated the role of the single immunoglobulin IL-1 receptor-related (SIGIRR) molecule, a negative regulator of TLR and IL-1R signaling, as a tumor suppressor to determine whether SIGIRR controls cell-cycle progression, genetic instability, and colon tumor initiation by modulating commensal TLR signaling in the gastrointestinal tract. Methods: We analyzed adenomatous polyposis coli (Apc) min/+/ Sigirr −/− mice for polyps, microadenomas, and anaphase bridge index. Commensal bacteria were depleted from mice with antibiotics. Akt, mammalian target of rapamycin (mTOR), and β-catenin pathways were examined by immunoblotting and immunohistochemistry. Loss of heterozygosity of Apc and expression of cytokines and proinflammatory mediators were measured by nonquantitative or quantitative polymerase chain reaction. Results: Apc min/+/ Sigirr −/− mice had increased loss of heterozygosity of Apc and microadenoma formation, resulting in spontaneous colonic polyposis, compared with Apc min/+ /Sigirr +/+ mice. The increased colonic tumorigenesis that occurred in the Apc min/+/ Sigirr −/− mice depended on the presence of commensal bacteria in the gastrointestinal tract. Cell proliferation and chromosomal instability increased in colon crypt cells of the Apc min/+/ Sigirr −/− mice. Akt, mTOR, and their substrates were hyperactivated in colon epithelium of Apc min/+/ Sigirr −/− mice in response to TLR or IL-1R ligands. Inhibition of the mTOR pathway by rapamycin reduced formation of microadenomas and polyps in the Apc min/+/ Sigirr −/− mice. Conclusions: SIGIRR acts as a tumor suppressor in the colon by inhibiting TLR-induced, mTOR-mediated cell-cycle progression and genetic instability. [Copyright &y& Elsevier]

The colon epithelium undergoes constant self-renewal in order to maintain its function as a nutrient sensor and a physical barrier from the commensal microbiota. Colon epithelium homeostasis is altered by inflammation and tissue injury/repair. In excess of which, contributes to the development of colon cancer. Here, we investigated the impact of IL-17A on the colon epithelium homeostasis and tumor development. IL-17A signals through a heterodimeric receptor complex composed of IL-17RA and IL-17RC. We found that the colon epithelium from IL-17RC-deficient mice displayed reduced proliferation, increased cell apoptosis and increased permeability after DSS challenge compared to control mice. Moreover, the IL-17RC-deficient mice developed significantly fewer colonic tumors compared to control mice in the AOM/DSS model of colitis-associated cancer. We then aimed to identify the cell-type responsible for IL-17A-mediated impact on homeostasis and tumorigenesis. Presumably, this IL-17-responsive cell population would sustain the initial mutation induced by carcinogen AOM, self replicate, and ultimately give rise to the neoplastic foci. Since the renewal of the colon epithelium relies upon a stem-cell niche (LGR5-positive cells) at the base of each crypt, we specifically ablated IL-17 signaling by deleting the IL-17R adaptor protein Act1 from this compartment. Following the AOM/DSS regimen the Act1CSC-KO mice developed significantly fewer colonic tumors compared to littermates. Mechanistically, IL-17A induced the activation of ERK5, ERK1/2 and JNK in colon epithelial cells. The activation of ERK5 and ERK1/2 were diminished in colon tissues of IL-17RC-deficient mice compared to that in the control mice with or without DSS treatment, implicating these MAPKs in IL-17R-dependent colon epithelium homeostasis. Furthermore, this pathway relied upon IL-17RC-dependent Act1 recruitment of TRAF4. We propose that IL-17R-Act1-TRAF4 cascade activates MAPKs in the LGR5-positive stem cells to promote regeneration after injury, consequently contributing to colon tumorigenesis by sustaining stem cells harboring a critical genetic lesion. [ABSTRACT FROM AUTHOR]

An abstract of the paper "Toll-Like Receptors are critical in controlling colonic inflammation and cancer," by Hui Xiao and colleagues is presented.