Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation, whereas immune competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs), induce inflammation, and, thereby, exclude microbes. The difference between macrophages and ocular surface epithelial cells could be due to their dissimilarity in coexistence with commensal bacteria. The unique innate immune response of the ocular surface epithelium might contribute to its coexistence with commensal bacteria. Moreover, we suspect that some ocular surface inflammatory disorders might be caused by abnormality of the mucosal innate immunity. We considered the possibility that there is an association between Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)--a severe variant of SJS--and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that interleukin-4 receptor (IL-4R) gene expression was different between patients with SJS/TEN and normal control subjects upon lipopolysaccharide (LPS) stimulation: it was downregulated in the former and slightly upregulated in the latter. Furthermore, expression of mRNA specific for IkappaBzeta and interleukin (IL)-1alpha was lower in patients with SJS/TEN than in normal controls after 1-hour culture. We next performed single nucleotide polymorphism (SNP) association analysis of IL-4R, IkappaBzeta, and IL1alpha genes and TLR2 and TLR3--genes associated with innate immunity--in 80 Japanese patients with SJS/TEN and 160 Japanese healthy volunteers. IL4R SNP Gln551Arg (rs.1801275) (P = 0.0004), TLR3 rs.3775296T/G SNP (P = 0.0001) and TLR3 rs.3775290A/G SNP (P = 0.009) showed a significant association with SJS/TEN. IkappaBzeta SNP rs.595788G/A showed a weak inverse association (P = 0.04). Genetic and environmental factors may play a role in an integrated etiology of SJS/TEN, and there is possibly an association between SJS/TEN and a disordered innate immunity.
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PMID:Innate immunity of the ocular surface and ocular surface inflammatory disorders. 1881 73

The inhibitory effect of interleukin-10 (IL-10), an anti-inflammatory cytokine, on lipopolysaccharide (LPS)-induced IL-6 production was characterized by simultaneous stimulation of RAW 264.7 cells with LPS and IL-10. The presence of IL-10 significantly inhibited LPS-induced IL-6 production at a transcriptional level. The expression of IkappaB-zeta, which promotes IL-6 production, was induced in response to LPS and it was definitely suppressed in the presence of IL-10. Further, IL-10 inhibited LPS-induced NF-kappaB activation. A pharmacological inhibitor of NF-kappaB prevented LPS-induced IkappaB-zeta expression, suggesting that IL-10 might inhibit LPS-induced IkappaB-zeta expression via the inactivation of NF-kappaB. In LPS- and IL-10-stimulated cells, the expression of Bcl-3 that inhibits NF-kappaB activation was significantly augmented. Introduction of Bcl-3 siRNA abolished IL-10-mediated IkappaB-zeta inhibition. In the presence of Bcl-3, siRNA IL-10 failed to inhibit LPS-induced IL-6 production. Therefore, it was suggested that Bcl-3 induced by IL-10 might reduce LPS-induced IkappaB-zeta activity via inactivation of NF-kappaB and that reduced IkappaB-zeta activity failed to promote LPS-induced IL-6 production.
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PMID:Interleukin (IL)-10 attenuates lipopolysaccharide-induced IL-6 production via inhibition of IkappaB-zeta activity by Bcl-3. 1958 95

The ocular surface epithelium serves a critical function as the defensive front line of the innate immune system. While the detection of microbes is arguably its most important task, an exaggerated host defense reaction to endogenous bacterial flora may initiate and perpetuate inflammatory mucosal responses. The ability of cells to recognize pathogen-associated molecular patterns (PAMPs) mainly depends on the expression of a family of Toll-like receptors (TLRs). A healthy ocular surface is not inflammatory, even though ocular surface epithelium is in constant contact with bacteria and bacterial products. In this study, we show that human ocular surface epithelial cells, both corneal and conjuctival epithelial cells, respond to viral double-stranded RNA mimic polyI:C to produce pro-inflammatory cytokines through TLR3, while they fail to respond functionally to lipopolysaccharide, a TLR4 ligand. Moreover, human ocular surface epithelium responds to flagellins from ocular pathogenic, but not ocular non-pathogenic bacteria, to produce pro-inflammatory cytokines through TLR5. Thus, ocular surface epithelial cells selectively respond to microbial components and induce limited inflammation; immune-competent cells can recognize microbial components through TLRs and induce the inflammation. The unique innate immune response of the ocular surface epithelium may contribute to its coexistence with commensal bacteria. Inflammatory bowel disease is thought to result from an abnormal response to the gut microbiota. Thus, we also considered the possibility of an association between ocular surface inflammation and a disordered innate immune response. IkappaBzeta is important for TLR signaling, in mice, its knock-out produced severe, spontaneous ocular surface inflammation, the eventual loss of goblet cells, and spontaneous perioral inflammation, suggesting that dysfunction/abnormality of innate immunity can lead to ocular surface inflammation.
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PMID:Innate immunity of the ocular surface. 1982 29

This review addresses three subjects: the innate immunity of the ocular surface epithelium, innate immunity and ocular surface inflammation, and Stevens-Johnson syndrome (SJS) and abnormality of innate immunity. In innate immunity of the ocular surface epithelium, ocular surface epithelial cells respond selectively to microbial components and induce limited inflammation, whereas immune-competent cells such as macrophages can recognize various microbial components through Toll-like receptors (TLRs) and induce inflammation to exclude the microbes. The difference between macrophages and ocular surface epithelial cells may be caused by the dissimilarity in the degree of coexistence with commensal bacteria. The unique innate immune response of ocular surface epithelium might contribute to coexistence with commensal bacteria. In innate immunity and ocular surface inflammation, we speculate that an abnormality in the proper innate immunity of the ocular surface may result in ocular surface inflammation. Our investigation shows that TLR3 positively regulates the late-phase reaction of experimental allergic conjunctivitis, which causes reduced eosinophilic conjunctival inflammation in TLR3KO (knockout) mice and pronounced eosinophilic conjunctival inflammation in TLR3Tg mice. We also demonstrate that human ocular surface epithelial cells can be induced to express many transcripts, including antiviral innate immune response-related genes and allergy-related genes, through polyI:C stimulation. Furthermore, we show that IkappaBzeta KO mice exhibit severe, spontaneous ocular surface inflammation accompanied by the eventual loss of almost all goblet cells and spontaneous perioral inflammation. IkappaBzeta is induced by diverse pathogen-associated molecular patterns and regulates nuclear factor-kappaB activity, possibly to prevent excessive inflammation in the presence of bacterial components. The spontaneous ocular surface inflammation observed in IkappaBzeta KO mice suggested that dysfunction/abnormality of innate immunity can play a role in ocular surface inflammation. In SJS and abnormality of innate immunity, we considered the possibility that there may be an association between SJS and a disordered innate immune response. In gene expression analysis of CD14 cells, we found that IL4R gene expression was different in patients with SJS/toxic epidermal necrolysis (TEN) and controls on lipopolysaccharide stimulation, being downregulated in patients with SJS/TEN and slightly upregulated in the controls. The expression of IkappaBzeta- and interleukin (IL)-1alpha-specific mRNA in patients with SJS/TEN was lower than in normal controls after 1-hour culture. Although SJS/TEN can be induced by drugs, not all individuals treated with these drugs developed SJS/TEN. Because the incidence of SJS/TEN is very low, we suspected a genetic predisposition and performed single-nucleotide polymorphism (SNP) association analysis using candidate genes associated with innate immunity, apoptosis, or allergy. We found that TLR3 SNP rs.3775296 and IL4R SNP rs.1801275 (Gln551Arg) were strongly associated (P<0.0005) with SJS/TEN with ocular surface complications, FasL rs.3830150 SNP was mildly associated (P<0.005), and IL13 rs.20541 (Arg110Gln) and IkappaBzeta SNP rs.595788G/A exhibited a weak association (P<0.05). Genetic and environmental factors may play a role in an integrated cause of SJS, and there is the possibility of an association between SJS and a disordered innate immunity.
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PMID:Ocular surface inflammation mediated by innate immunity. 2070 56


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