Regulation of TNF-α and IFN-γ induced CXCL10 expression: participation of the airway smooth muscle in the pulmonary inflammatory response in chronic obstructive pulmonary disease

The chemokine CXCL10 is produced by many inflammatory cells found in the diseased lung and has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). The present study demonstrates elevated CXCL10 protein in the lungs of COPD patients, which appears histologically in airway smooth muscle (hASM). In primary cultured hASM cells taken from normal donors, CXCL10 protein expression was induced by IFN-γ and TNF-α, cytokines reported as elevated in COPD, and a synergistic response was obtained when they were combined. TNF-α stimulation of hASM enhanced accumulation of CXCL10 mRNA, indicating regulation at the transcriptional level, while IFN-γ stimulation resulted in a smaller accumulation of CXCL10 mRNA. When these cytokines were applied simultaneously, an additive effect was obtained. TNF-α-induced CXCL10 expression in hASM was dependent on NFκB activation, and a salicylanilide NFκB inhibitor blocked the CXCL10 expression. In contrast, IFN-γ stimulation resulted in transient NFκB activation, and the inhibitor had little effect on CXCL10 expression. When these cytokines were added simultaneously, NFκB was activated earlier and lasted longer, and the effect was blocked by the inhibitor. These data demonstrate a potential active role for hASM in pulmonary inflammatory diseases such as COPD by producing CXCL10.