Cyclooxygenase and cytokine regulation in lung fibroblasts activated with viral versus bacterial pathogen associated molecular patterns

• Human lung fibroblasts are particularly sensitive to activation of Toll-like receptor 3.
• Cyclooxygenase inhibition abolishes PGE2 and enhances IL-8 and IP-10 release from human lung fibroblasts.
• Cyclooxygenase-1 or cyclooxygenase-2 activity limit mouse lung fibroblast KC levels.
• PGE2 levels correlate to KC and IP-10 release from human lung fibroblasts, but not mouse lung fibroblasts.

Cyclooxygenase (COX) is required for prostanoid (e.g. prostaglandin PGE2) production. Constitutive COX-1 and inducible COX-2 are implicated in lung diseases, such as idiopathic pulmonary fibrosis (IPF). Using lung fibroblasts from humans and wild type, COX-1−/− and COX-2−/− mice, we investigated how COX activity modulates cell growth and inflammatory responses induced by activators of Toll-like receptors (TLRs) 1–8. In mouse tissue, PGE2 release from fresh lung was COX-1 driven, in lung in culture (24 h) COX-1 and COX-2 driven, and from proliferating lung fibroblasts exclusively COX-2 driven. COX-2 limited proliferation in lung fibroblasts and both isoforms limited KC release induced by a range of TLR agonists. Less effect of COX was seen on TLR-induced IP-10 release. In human lung fibroblasts inhibition of COX with diclofenac was associated with increased release of IL-8 and IP-10. Our results may have implications for the treatment of IPF.