Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We report here that Janus kinase 3 (Jak3) is a primary response gene for interleukin-6 (IL-6) in macrophage differentiation, and ectopic overexpression of Jak3 accelerates monocytic differentiation of normal mouse bone marrow cells stimulated with cytokines. Furthermore, we show that incubation of normal mouse bone marrow cells with a JAK3-specific inhibitor results in profound inhibition of myeloid colony formation in response to granulocyte-macrophage colony-stimulating factor or the combination of stem cell factor, IL-3, and IL-6. In addition, mutagenesis of the Jak3 promoter has revealed that Sp1 binding sites within a -67 to -85 element and a signal transducer and activator of transcription (Stat) binding site at position -44 to -53 are critical for activation of Jak3 transcription in murine M1 myeloid leukemia cells stimulated with IL-6. Electrophoretic mobility shift assay (EMSA) analysis has demonstrated that Sp1 can bind to the -67 to -85 element and Stat3 can bind to the -44 to -53 STAT site in IL-6-stimulated M1 cells. Additionally, ectopic overexpression of Stat3 enhanced Jak3 promoter activity in M1 cells. This mechanism of activation of the murine Jak3 promoter in myeloid cells is distinct from a recently reported mechanism of activation of the human JAK3 promoter in activated T cells.
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PMID:Mechanisms associated with IL-6-induced up-regulation of Jak3 and its role in monocytic differentiation. 1497 41

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) oncoprotein has been shown to mediate activation of the signal transducer and activator of transcription 3 (STAT3). In the present study, we delineated the mechanism by which LMP1 stimulates STAT3 in a human nasopharyngeal carcinoma (NPC) cell line. LMP1 stimulated STAT3 Tyr 705-dependent nuclear accumulation, as well as the phosphorylation of STAT3 at both Tyr 705 and Ser 727. Treatment of cells with interleukin-6 neutralizing antibody inhibited the phosphorylation of STAT3 Tyr 705 and Ser 727. The differential phosphorylation of STAT3 was found to be a result of activation of Janus kinase 3 (JAK3) and extracellular signal-regulated kinase (ERK). The biological significance of JAK3-mediated activation of STAT3 Tyr 705 phosphorylation was further assessed by treating the cells with an inhibitor (WHI-P131) of JAK3. Inhibition of ERK activity by an inhibitor (PD98059) of MAPK/extracellular signal-regulated kinase kinase (MEK1) decreased the LMP1-induced activation of STAT3 Ser 727. Furthermore, immunohistochemical analysis showed an increased nuclear STAT3 Tyr 705 staining in LMP1-positive cells and STAT3 Tyr 705 phosphorylation related to NPC stages III and IV. Demonstration of the involvement of different kinases in LMP1-induced STAT3 activation supports the involvement of the JAK/STAT and mitogen-activated protein kinase (MAPK)/ERK signaling pathways in the regulation of STAT3 activation by LMP1.
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PMID:Phosphorylation and nuclear translocation of STAT3 regulated by the Epstein-Barr virus latent membrane protein 1 in nasopharyngeal carcinoma. 1820 81

Elevated concentrations of IL-6 (interleukin-6) and sIL-6r (soluble IL-6 receptor) in the synovial fluid and serum of patients with arthritis have been implicated in joint cartilage destruction. This study examined the effects of IL-6 and sIL-6r on the expression of MMPs (matrix metalloproteinases), TIMPs (tissue inhibitor of metalloproteinases), the plasminogen activation system including tPA (tissue-type PA), uPA (urokinase-type PA) and PAI-1 (PA inhibitor type 1) using chondrocytes derived from normal human femur cartilage. The cells were cultured with or without 50 ng/ml IL-6 and/or 30 ng/ml sIL-6r in the presence or absence of the JAK3 (Janus kinase 3) inhibitor WHI-P131 or the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular signal protein kinase) kinase] inhibitor PD98059 for up to 28 days. The expression of MMPs, TIMPs, uPA, tPA and PAI-1 was investigated at the mRNA and protein levels. MMP protein expression and pSTAT3 (phosphorylation of signal transducer and activator of transcription 3) and pERK (phosphorylation of ERK) were also measured. Treatment with both IL-6 and sIL-6r markedly increased the expression of MMP-1, MMP-13, TIMP-1 and PAI-1, while significantly decreasing the expression of tPA and uPA and stimulating pSTAT3 and pERK. Adding WHI-P131 or PD98059 decreased IL-6 and sIL-6r enhancement of MMP-1, -3 and -13. The results suggest that IL-6 and sIL-6r stimulate the production of MMPs and their inhibitor via JAK-STAT and ERK-MAPK signalling in chondrocytes.
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PMID:IL-6 and soluble IL-6 receptor stimulate the production of MMPs and their inhibitors via JAK-STAT and ERK-MAPK signalling in human chondrocytes. 2208 78