Sex-specific COX-2/CREB/ER signaling underlies male susceptibility to pulmonary fibrosis in rheumatoid arthritis-associated interstitial lung disease.

Objectives: Rheumatoid arthritis is more prevalent in women than in men, but rheumatoid arthritis-associated interstitial lung disease occurs more frequently and with greater severity in men. To address this paradox, we investigated whether sex- and tissue-specific regulation of the cyclooxygenase-2/cyclic AMP-responsive element-binding protein/estrogen receptor axis contributes to the distinct rheumatoid arthritis-associated interstitial lung disease manifestations. Methods: Curdlan-induced SKG mice were used to assess sex-dependent disease manifestations. Arthritis severity was evaluated both clinically and histologically. Pulmonary inflammation and fibrosis were analyzed histologically, whereas gene and protein expression levels were assessed by quantitative reverse transcription polymerase chain reaction and western blotting. Results: Female mice developed earlier and more severe joint arthritis, whereas male mice exhibited greater pulmonary inflammation and fibrosis. These sex- and tissue-specific differences were supported by differential expression of fibrosis-related genes (fibronectin, collagen type I alpha 1 chain, vimentin, mucin-1, and E-cadherin). Lung tissues from males showed higher estrogen receptor α and estrogen receptor β expression, while joint estrogen receptor expression was predominantly higher in females, and no sex-related differences were observed in intestinal estrogen receptor expression. Consistent with estrogen receptor expression patterns, cyclooxygenase-2 and cyclic AMP-responsive element-binding protein expression were elevated in male lungs. Collectively, these findings suggest that sex- and organ-specific activation of the cyclooxygenase-2/cyclic AMP-responsive element-binding protein/estrogen receptor axis contributes to the inflammatory patterns in Rheumatoid arthritis-associated interstitial lung disease. Conclusion: Our findings suggest that cyclooxygenase-2/cyclic AMP-responsive element-binding protein/estrogen receptor pathway activation in male lungs may explain their increased tendency toward fibrotic remodeling, whereas enhanced estrogen receptor signaling in female joints may contribute to more severe arthritis. These observations raise the possibility that sex- and tissue-specific regulation of this signaling axis influences rheumatoid arthritis-associated interstitial lung disease pathogenesis and may inform future research on therapeutic strategies.