Point mutation of tyrosine 759 of the IL-6 family cytokine receptor, gp130, augments collagen-induced arthritis in DBA/1J mice

<p>Abstract</p> <p>Background</p> <p>Knock-in mice (gp130F759) with a Y759F point mutation in gp130, a signal transducing receptor subunit shared by members of the IL-6 cytokine family, show sustained activation of STAT3, enhanced acute-phase or immune responses, and autoimmune arthritis. We conducted a detailed analysis of collagen-induced arthritis (CIA) in gp130F759 with a DBA/1J background (D/J.gp130F759).</p> <p>Methods</p> <p>We backcrossed gp130F759 to C57BL/6 and DBA/1J, and compared the pathologic changes, including occurrence of arthritis, in the two distinct genetic backgrounds. We analyzed CIA in D/J.gp130F759 and investigated the effects of methotrexate (MTX) on CIA.</p> <p>Results</p> <p>C57BL/6 background gp130F759 mice, but not D/J.gp130F759, spontaneously developed polyarthritis and glomerulonephritis. On the other hand, keratitis of the eyes only developed in D/J.gp130F759, indicating the influence of genetic background on disease development in gp130F759 mice. Resistance of the DBA/1J background against spontaneous arthritis urged us to examine CIA in D/J.gp130F759. CIA in D/J.gp130F759 was more severe, with greater bone destruction, than the control mice. After collagen immunization, splenomegaly and serum levels of rheumatoid factor and anti-DNA antibody were augmented in D/J.gp130F759. Bio-Plex analysis of serum cytokines revealed increased IL-12p40 and PDGF-BB before immunization, and increased levels of IFN-γ, IL-17, TNF-α, IL-9, and MIP-1β 8 days after the booster dose. IL-6 and PDGF-BB in D/J.gp130F759 showed distinct kinetics from the other cytokines; higher levels were observed after arthritis development. MTX partially attenuated the development of arthritis and inhibited bone destruction in D/J.gp130F759, with reduction of anti-type II collagen antibody levels, suggesting that MTX mainly affects antigen-specific immune responses in CIA.</p> <p>Conclusion</p> <p>The Tyr-759 point mutation of the IL-6 family cytokine receptor subunit, gp130, caused autoimmune disease, and this was also influenced by the genetic background. CIA in D/J.gp130F759 is useful for evaluating drugs in a relatively short period because sustained activation of STAT3 may enhance the disease symptoms.</p

The influence of nicotine on granulocytic differentiation - Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release

NRC publication: Ye

IL-9 and its receptor in allergic and nonallergic lung disease: Increased expression in asthma

Background: Bronchial asthma is a chronic inflammatory disease associated with genetic components. Recently IL-9 has been reported as a candidate gene for asthma and to be associated with bronchial hyperresponsiveness and elevated levels of total serum IgE. Objective: To investigate the contribution of IL-9 to the pathogenesis of asthma, we examined the expression of IL-9 and its receptor (IL-9R) in bronchial tissue from subjects with atopic asthma (n = 10), chronic bronchitis (n = 11), and sarcoidosis (n = 9) and from atopic (n = 7) and nonatopic (n = 10) healthy control subjects. Methods: Bronchial biopsy specimens were examined for the presence of IL-9 and IL-9R protein and messenger RNA (mRNA) by immunocytochemistry and in situ hybridization, respectively. To phenotype the cells expressing IL-9 in asthmatic tissue, combined in situ hybridization and immunocytochemistry was also performed. Results: There was a highly significant difference (P .05), IL-9R immunoreactivity was significantly higher in asthmatic compared with control subjects. Furthermore, IL-9 mRNA expression levels were also significantly correlated with FEV1 (P < .05) and the airway responsiveness to methacholine producing a 20% fall in FEV1 (P < .01). The cells expressing IL-9 mRNA in asthmatic tissue were CD3+ lymphocytes (68%), major basic protein+ eosinophils (16%), and elastase+ neutrophils (8%). Conclusion: The results of this study demonstrate the potential of IL-9 to be a marker for atopic asthma and furthermore suggest an important role for this cytokine in the pathophysiologic mechanisms of this disease. (J Allergy Clin Immunol 2000;105:108-15.

The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release-6

HL-60 cells stimulated with LPS (1.0 μg ml) plus nicotine (10M, Lane 2); compared to LPS alone (Lane 1). Nicotine-induced augmentation of LPS-induced MMP-9 activity is abrogated by pre-incubation of DMSO-differentiated HL-60 cells with an α7-type nAChR inhibitor (α-bungarotoxin, 200 ng ml, Lane 3). Relative fold increases (mean, s.d.) in MMP-9 gelatinolytic activity were quantified by densitometry (= 5, * < 0.05, < 0.01). Error bars represent standard deviations of the mean.<p><b>Copyright information:</b></p><p>Taken from "The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release"</p><p>http://www.biomedcentral.com/1471-2121/9/19</p><p>BMC Cell Biology 2008;9():19-19.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2375863.</p><p></p

The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release-5

N (< 0.01). This suppression of bacterial killing was reversed by pre-treating DMSO-induced HL-60 cells with the nAChR-antagonist α-bungarotoxin (α-BTX, 500 ng ml). Error bars represent standard deviations of the mean, = 3.<p><b>Copyright information:</b></p><p>Taken from "The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release"</p><p>http://www.biomedcentral.com/1471-2121/9/19</p><p>BMC Cell Biology 2008;9():19-19.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2375863.</p><p></p

The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release-0

μg) of five day, DMSO-induced HL-60 cells without nicotine, or with 10M nicotine, or with 10M nicotine treatment, respectively. α7 nAChR-specific antibodies (Santa Cruz SC-5544) bound to protein bands exhibiting a relative molecular mass of 55.0 KDa in all lanes. Densitometric analysis () revealed that α7 nAChR-specific band intensities were significantly increased in the DMSO-treated samples, relative to promyelocytic cells (= 5, *< 0.05), but that this differentiation-associated increase α7 nAChR protein level was not influenced by nicotine exposure during differentiation in any statistically significant manner. α7 nAChR Immunofluorescence staining (×1000): Fixed five-day, DMSO-induced HL-60 cells were incubated with a polyclonal rabbit anti-α7 antibody (Santa Cruz SC-5544) before staining with a FITC-conjugated anti-rabbit antibody (Santa Cruz SC-2253). α7 nAChR-specific staining was evenly distributed across the cells. A similar cellular distribution of α7 nAChR was observed in promyelocytic cells (). Negative control for α7 nAChR Immunofluorescence staining (×1000).<p><b>Copyright information:</b></p><p>Taken from "The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release"</p><p>http://www.biomedcentral.com/1471-2121/9/19</p><p>BMC Cell Biology 2008;9():19-19.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2375863.</p><p></p

The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release-7

Rations are significantly increased in smokers compared to non-smokers (* < 0.05). Error bars represent the interquartile range.<p><b>Copyright information:</b></p><p>Taken from "The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release"</p><p>http://www.biomedcentral.com/1471-2121/9/19</p><p>BMC Cell Biology 2008;9():19-19.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2375863.</p><p></p

The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release-4

HL-60 cells was reduced by as much as 48% (= 12, < 0.001 compared to DMSO-only control cells). Error bars represent standard deviations of the mean.<p><b>Copyright information:</b></p><p>Taken from "The influence of nicotine on granulocytic differentiation – Inhibition of the oxidative burst and bacterial killing and increased matrix metalloproteinase-9 release"</p><p>http://www.biomedcentral.com/1471-2121/9/19</p><p>BMC Cell Biology 2008;9():19-19.</p><p>Published online 15 Apr 2008</p><p>PMCID:PMC2375863.</p><p></p