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

Endotoxin and proinflammatory cytokines such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) induce a state of GH resistance. A new family of suppressors of cytokine signaling (SOCS), induced by cytokines activating the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, has been recently identified as a negative feedback loop of intracellular signaling. Overexpression of some SOCS (SOCS-3, CIS, and SOCS-2) has been reported to inhibit the JAK-STAT pathway stimulated by GH. To assess the possible role of these three SOCS proteins in the GH resistance induced by endotoxin and cytokines, we investigated the regulation of their gene expression by endotoxin and GH in rat liver and by proinflammatory cytokines and GH in primary culture hepatocytes. Both GH and lipopolysaccharide induced the three SOCS messenger RNAs (mRNAs) in vivo. In vitro, GH also increased the liver mRNAs encoding SOCS-2, SOCS-3, and CIS. Although IL-1/beta and TNFalpha alone induced only weakly the expression of SOCS-3 and CIS, these cytokines strongly potentiated the induction of these two SOCS by GH. In contrast, IL-6 alone markedly induced SOCS-3 mRNA, but did not potentiate the GH action on SOCS-3 and CIS mRNAs. The GH induction of SOCS-2 was not potentiated by any of these cytokines. Considering the ability of these SOCS to inhibit the JAK-STAT pathway induced by GH, these results suggest that the overexpression of SOCS-3 and CIS mRNAs induced by IL-1beta and TNFalpha or by endotoxin in vivo may play a role in the GH resistance induced by sepsis.
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PMID:Potentiation of growth hormone-induced liver suppressors of cytokine signaling messenger ribonucleic acid by cytokines. 1101 23

Intravesical bacillus Calmette-Guerin (BCG) is a treatment for transitional cell carcinoma (TCC) and carcinoma in situ (cis) of the urinary bladder, but some patients remain refractory. The mechanism of cancer clearance is not known, but T cells are thought to play a contributory role. Tissue dendritic cells (DCs) are known to initiate antigen-specific immune responses following activation of receptors, which recognise molecular patterns on the surface of microorganisms. A family of these receptors, the toll-like receptors (TLRs), are also crucial for activating DC to produce cytokines that polarise the T-cell response towards a T helper (Th)1 or Th2 phenotype. This study compared the potential of intact BCG to activate DC with that of the defined TLR4 ligand lipopolysaccharide (LPS) and the TLR9 ligand CpG-oligonucleotide. It was found that all three stimuli efficiently activated normal DC, but cells expressing a mutant TLR4 responded poorly to stimulation with LPS. Importantly, stimulation with BCG induced both IL-12 and IL-10, suggesting subsequent development of a poorly focused T-cell immune response containing both Th1 and Th2 immune function. By contrast, LPS- and CpG-oligonucleotides induced only IL-12, indicating the potential to produce a Th1 response, which is likely to clear cancer most efficiently. Given the toxicity of LPS, our data suggest that CpG-oligonucleotides may be beneficial for intravesical therapy of bladder cancer.
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PMID:Polarisation of a T-helper cell immune response by activation of dendritic cells with CpG-containing oligonucleotides: a potential therapeutic regime for bladder cancer immunotherapy. 1467 12

Bacterial lipopolysaccharide (LPS) triggers innate immune responses through the Toll-like receptor (TLR) 4. Regulation of TLR signaling is a key step for inflammation, septic shock and innate/adaptive immunity. TLR signaling is shown to be regulated by cytokines, such as interferon-gamma (positive) and interleukin-10 and IL-4 (negative). However, molecular mechanisms of the regulation of LPS signaling by cytokines have not been clarified. Cytokine signaling is regulated by CIS/SOCS family proteins. Both SOCS1 and SOCS3 can inhibit JAK tyrosine kinase activity. We demonstrate that SOCS1 and SOCS3 play an important regulatory role in macrophages and dendritic cells (DCs) by modulating TLR signaling. SOCS1 negatively regulates not only the JAK/STAT pathway, but also the TLR-NF-kappaB pathway. SOCS3 protein was strongly induced by both IL-6 and IL-10 in the presence of LPS, but selectively inhibited IL-6 signaling. Therefore lack of SOCS3 gene in macrophages resulted in suppression of TLR signaling by hyperactivation of STAT3.
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PMID:[Regulation of cytokine and toll-like receptor signaling by SOCS family genes]. 1559 84