TY - JOUR T1 - Alveolar macrophages activate STAT3 in epithelial cells via gp130 dependant steroid insensitive mechanism JF - European Respiratory Journal JO - Eur Respir J VL - 42 IS - Suppl 57 SP - P3867 AU - Jonathan Plumb AU - Arjun Ravi AU - George Booth AU - Dave Singh Y1 - 2013/09/01 UR - http://erj.ersjournals.com/content/42/Suppl_57/P3867.abstract N2 - RationaleIncreased production of the IL-6 cytokine family is a hallmark of many human chronic inflammatory diseases including COPD. Elevated IL-6 levels are associated with increased mortality, faster rate of decline in lung function and increased exacerbation frequency in COPD. IL-6 ligation to the IL-6 receptor complex induces the JAK-STAT signalling cascade resulting in the activation of the transcription factor STAT3. Aims: to determine whether STAT3 is activated within the small airways of COPD patients.MethodsSTAT3 phosphorylation (STAT3p) was analysed by immunohistochemistry in small airway samples from 44 patients (COPD n = 24, smoking controls (S) n = 10 and non-smoking controls (NS) n = 10) undergoing surgical resection. BEAS-2B cells were cultured in conditioned media from alveolar macrophages (AM) +/- LPS as well as induced sputum supernatants; STAT3p was analysed by Western blot.ResultsIncreased levels of STAT3p were detected within the small airways of COPD patients compared to S and NS controls. There were also increased numbers of STAT3p+ cells within the sub-epithelium of COPD small airways (mean 820 cells/mm2) compared to S (mean 403 cells/mm2) and NS (mean 348 cells/mm2) (ANOVA p<0.001). AMs were devoid of STAT3p. Conditioned media from LPS stimulated AMs, as well as sputum supernatant, induced STAT3p. Blockade of STAT3 activation was observed using a pan-gp130Mab (B-R3) but not corticosteroids.ConclusionWe propose that IL-6 released by AM activates STAT3 in the small airways of COPD patients in a corticosteroid resistant manner. Selective targeting of the IL-6-STAT3-gp130 signalling axis may provide a useful novel therapy in COPD. ER -