Gene Set: SEKI_INFLAMMATORY_RESPONSE_LPS_DN

Standard name SEKI_INFLAMMATORY_RESPONSE_LPS_DN
Systematic name M1980
Brief description Genes down-regulated in hepatic stellar cells after stimulation with bacterial lipopolysacharide (LPS).
Full description or abstract Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.
Collection C2: curated gene sets
      CGP: chemical and genetic perturbations
Source publication Pubmed 17952090   Authors: Seki E,De Minicis S,Osterreicher CH,Kluwe J,Osawa Y,Brenner DA,Schwabe RF
Exact source Table 1S: Fold change < 0.5
Related gene sets (show 1 additional gene sets from the source publication)

(show 1 gene sets from the same authors)
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Organism Mus musculus
Contributed by Jessica Robertson (Broad Institute)
Source platform Mouse430_2
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Compendia expression profiles Human tissue compendium (Novartis)
NCI-60 cell lines (National Cancer Institute)
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Version history 3.0: First introduced

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