Electrophilic PPARγ Ligands Attenuate IL-1β and Silica-Induced Inflammatory Mediator Production in Human Lung Fibroblasts via a PPARγ-Independent Mechanism

Acute and chronic lung inflammation is associated with numerous important disease pathologies including asthma, chronic obstructive pulmonary disease and silicosis. Lung fibroblasts are a novel and important target of anti-inflammatory therapy, as they orchestrate, respond to, and amplify inflammatory cascades and are the key cell in the pathogenesis of lung fibrosis. Peroxisome proliferator-activated receptor gamma (PPAR γ ) ligands are small molecules that induce anti-inflammatory responses in a variety of tissues. Here, we report for the first time that PPAR γ ligands have potent anti-inflammatory effects on human lung fibroblasts. 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO) and 15-deoxy-Δ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) inhibit production of the inflammatory mediators interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), COX-2, and prostaglandin (PG)E 2 in primary human lung fibroblasts stimulated with either IL-1 β or silica. The anti-inflammatory properties of these molecules are not blocked by the PPAR γ antagonist GW9662 and thus are largely PPAR γ independent. However, they are dependent on the presence of an electrophilic carbon. CDDO and 15d-PGJ 2 , but not rosiglitazone, inhibited NF- κ B activity. These results demonstrate that CDDO and 15d-PGJ 2 are potent attenuators of proinflammatory responses in lung fibroblasts and suggest that these molecules should be explored as the basis for novel, targeted anti-inflammatory therapies in the lung and other organs.