SUMMARY Tight regulation of NF-κB signaling is essential for innate and adaptive immune responses, yet the molecular mechanisms responsible for its negative regulation are not completely understood. Here we report that NLRX1, a NOD-like receptor family member, negatively regulates Toll-like receptor-mediated NF-κB activation. NLRX1 interacts with TRAF6 or IκB kinase (IKK) in an activation signal-dependent fashion. Upon LPS stimulation, NLRX1 is rapidly ubiquitinated, disassociates from TRAF6 and then binds to the IKK complex, resulting in inhibition of IKKα/β phosphorylation and NF-κB activation. Knockdown of NLRX1 in various cell types markedly enhances IKK phosphorylation and the production of NF-κB-responsive cytokines after LPS stimulation. We further provide in vivo evidence that NLRX1 knockdown in mice markedly enhances susceptibility to LPS-induced septic shock and plasma IL-6 level. Our study identifies a previously unrecognized role for NLRX1 in the negative regulation of TLR-induced NF-κB activation by dynamically interacting with TRAF6 and the IKK complex.

SUMMARY Stringent control of NF-κB and mitogen-activated protein kinase (MAPK) signaling is critical during innate immune responses. TGF-β activated kinase-1 (TAK1) is essential for NF-κB activation in T and B cells but has precisely the opposite activity in myeloid cells. Specific deletion of TAK1 (Map3k7ΔM/ΔM) led to development of splenomegaly and lymphomegaly associated with neutrophilia. Compared with wild-type cells, TAK1-deficient neutrophils enhanced the phosphorylation of the kinases IKK, p38, and JNK and the production of interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and reactive oxygen species (ROS) after lipopolysaccharide (LPS) stimulation. Map3k7ΔM/ΔM mice were significantly more susceptible to LPS-induced septic shock and produced higher amounts of IL-1β, IL-6, and TNF-α in plasma than do wild-type mice. Specific ablation of p38 rescued the phenotype and functional properties of Map3k7ΔM/ΔM mice. Our findings identify a previously unrecognized role of TAK1 as a negative regulator of p38 and IKK activation in a cell type-specific manner.

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Renal cell carcinoma (RCC) is the most common type of kidney cancer in adults and accounts for ~80% of all kidney cancer cases. However, the pathogenesis of RCC has not yet been fully elucidated. To interpret the pathogenesis of RCC at the molecular level, gene expression data and bio-informatics methods were used to identify RCC associated genes. Gene expression data was downloaded from Gene Expression Omnibus (GEO) database and identified differentially coexpressed genes (DCGs) and dysfunctional pathways in RCC patients compared with controls. In addition, a regulatory network was constructed using the known regulatory data between transcription factors (TFs) and target genes in the University of California Santa Cruz (UCSC) Genome Browser () and the regulatory impact factor of each TF was calculated. A total of 258,0427 pairs of DCGs were identified. The regulatory network contained 1,525 pairs of regulatory associations between 126 TFs and 1,259 target genes and these genes were mainly enriched in cancer pathways, ErbB and MAPK. In the regulatory network, the 10 most strongly associated TFs were FOXC1, GATA3, ESR1, FOXL1, PATZ1, MYB, STAT5A, EGR2, EGR3 and PELP1. GATA3, ERG and MYB serve important roles in RCC while FOXC1, ESR1, FOXL1, PATZ1, STAT5A and PELP1 may be potential genes associated with RCC. In conclusion, the present study constructed a regulatory network and screened out several TFs that may be used as molecular biomarkers of RCC. However, future studies are needed to confirm the findings of the present study.

clinical application of doxorubicin (doX) is hampered by its potential cardiotoxicity, however angiotensin receptor blockers could attenuate doX-induced cardiomyopathy. The present study tested the hypothesis that simultaneous administration of valsartan (Val) with doX could prevent doX-induced myocardial injury by modulating myocardial nad(P)H oxidase (noX) expression in rats. eight-week-old male Sprague-dawley rats were randomly divided into control (con), doX, and doX+Val groups. after 10 weeks, surviving rats underwent echocardiography examination, myocardial mrna and protein expression detection of noX1, noX2 and noX4. H9c2 cells were used to perform in vitro experiments, reactive oxygen species (roS) production and apoptosis were observed under the conditions of down-or upregulation of noX2 and noX4 in doX-and DOX+Val-treated H9C2 cells. Cardiac function was significantly improved, pathological lesion and collagen volume fraction were significantly reduced in the DOX+Val group compared with the doX group (all P<0.05). Myocardial protein and mRNA expression of NOX2 and NOX4 was significantly downregulated in doX+Val group compared with in the doX group (all P<0.05). In vitro, roS production and apoptosis in doX-treated H9c2 cells was significantly reduced by noX2-small interfering (si)rna and noX4-sirna, and significantly increased by overexpressing NOX2 and NOX4. To conclude, Val applied simultaneously with doX could prevent doX-induced myocardial injury and reduce oxidative stress by downregulating the myocardial expression of noX2 and noX4 in rats.