PPAR‐α contributes to the anti‐inflammatory activity of 17β‐estradiol

Several lines of evidence support the concept that estrogens have anti‐inflammatory action. 17β‐estradiol (E2) significantly decreased the induction of iNOS in vitro as well as reduced the development of acute lung injury in rats. Moreover, it has been previously shown that estrogen signaling cross‐talked with peroxisome proliferator‐activated receptors (PPARs). Our data in experimental models of acute inflammation show that mice lacking PPAR‐α (PPAR‐αKO) developed an increased inflammation compared with wild‐type (WT) mice. With the aim to characterize the role of PPAR‐α in estrogen‐mediated anti‐inflammatory activity, we examined the efficacy of E2 in an experimental model of lung inflammation, such as carrageenan‐induced pleurisy, comparing ovariectomized PPAR‐αKO and WT mice. Results indicated that E2‐mediated anti‐inflammatory activity is weakened in PPAR‐αKO mice compared with WT group. In particular, E2 was less effective in PPAR‐αKO compared with WT mice in inhibition of cell migration as well as lung injury, NF‐êB activation, TNF‐α production, and iNOS activation. Macrophages from PPAR‐αKO were less susceptible to E2‐induced iNOS inhibition in vitro compared with macrophages from WT mice. Moreover, PPAR‐α was required for estrogen receptor up‐regulation, following E2 treatment. These results show for the first time that PPAR‐α contributes to the anti‐inflammatory activity of E2.