Inhibition of IRAK4 suppresses chemokine release from human bronchial epithelial cells

Rationale: COPD is characterized by chronic pulmonary inflammation associated with release of inflammatory mediators including IL-1β, CXCL8 and IL-6, which sustain the inflammatory process and lead to tissue damage. IRAK-4 (interleukin-1 receptor-associated kinase 4), mediates the innate immune response downstream of activation of IL-1β and toll-like receptors, hence inhibition of this pathway may be anti-inflammatory. This study investigated the effect of IRAK4 inhibitors on chemokine production from human bronchial epithelial cells. Methods: Beas-2B and primary human bronchial epithelial cells (HBEC) were pre-treated with IRAK4 inhibitors PFE1-3 or dexamethasone (DEX) prior to stimulation with IL1-β. After 24h, cytokines were measured by ELISA. Results: IRAK4 inhibitors attenuated IL-1[beta-stimulated] release of CXCL8 and IL-6 from both Beas-2B and HBEC. IRAK4 inhibitors were more potent than DEX (Table 1) and this effect was more prominent in HBEC with respect to IL-6 release. Conclusions : IRAK4 inhibition attenuates inflammatory cytokine release from epithelial cells and may be a novel therapeutic strategy for inflammatory lung diseases.