Effects of JAK-STAT inhibitors on glucocorticosteroid resistant release of CXCR3 chemokines from human bronchial epithelial cells

COPD is associated with glucocorticosteroid insensitive inflammation. CXCR3 chemokines are elevated in COPD and may drive recruitment of CD8+ lymphocytes. Expression of CXCR3 chemokines is regulated by IFNγ. This study investigated the effect of JAK-STAT inhibitors PF95 and PF13 on CXCR3 chemokine production from human bronchial epithelial cells. Beas-2B and primary human bronchial epithelial cells (HBEC) were pre-treated with PF95, PF13, or Dexamethasone (DEX) then stimulated with IFNγ or IFNγ+TNFα. After 24h, cytokines were measured by ELISA. Inhibition of the JAK-STAT pathway was measured by immunoblotting for phosphorylated and total STAT-1 and STAT DNA binding using Trans-AM kits. DEX had no effect on the release of CXCL9, 10 or 11, however all were inhibited by the JAK-STAT inhibitors stimulated with either IFNγ or IFNγ+TNFα (Table 1). HBEC responded similarly to Beas-2B. Both inhibitors attenuated phosphorylation of STAT-1 in a concentration dependent manner. DNA binding of STAT-1 and STAT-3was inhibited but not of STAT5a or STAT5b. JAK-STAT inhibitors therefore attenuate release of CXCR3 chemokines from airway epithelial cells under conditions of glucocorticosteroid insensitivity and have potential as a new anti-inflammatory treatment in COPD patients.