The group VIA calcium‐independent phospholipase A2 and NFATc4 pathway mediates IL‐1β‐induced expression of chemokines CCL2 and CXCL10 in rat fibroblasts
2018
Kuwata, Hiroshi | Yuzurihara, Chihiro | Kinoshita, Natsumi | Taki, Yuki | Ikegami, Yuki | Washio, Sana | Hirakawa, Yushi | Yoda, Emiko | Aiuchi, Toshihiro | Itabe, Hiroyuki | Nakatani, Yoshihito | Hara, Shuntaro
Chemokines are secreted proteins that regulate cell migration and are involved in inflammatory and immune responses. Here, we sought to define the functional crosstalk between the lipid signaling and chemokine signaling. We obtained evidence that the induction of some chemokines is regulated by group VIA calcium‐independent phospholipase A₂β (iPLA₂β) in IL‐1β‐stimulated rat fibroblastic 3Y1 cells. Treatment of 3Y1 cells with IL‐1β elicited an increased release of chemotactic factor(s) for monocytic THP‐1 cells into culture medium in a time‐dependent manner. Inhibitor studies revealed that an intracellular PLA₂ inhibitor, arachidonoyl trifluoromethyl ketone (AACOCF₃), but not the cyclooxygenase inhibitor indomethacin, attenuated the release of chemotactic factor(s). The chemotactic activity was inactivated by treatment with either heat or proteinase K, suggesting this chemotactic factor(s) is a proteinaceous factor(s). We purified the chemotactic factor(s) from the conditioned medium of IL‐1β‐stimulated 3Y1 cells using a heparin column and identified several chemokines, including CCL2 and CXCL10. The inducible expressions of CCL2 and CXCL10 were significantly attenuated by pretreatment with AACOCF₃. Gene silencing using siRNA revealed that the inductions of CCL2 and CXCL10 were attenuated by iPLA₂β knockdown. Additionally, the transcriptional activation of nuclear factor of activated T‐cell proteins (NFATs), but not nuclear factor‐κB, by IL‐1β stimulation was markedly attenuated by the iPLA₂ inhibitor bromoenol lactone, and NFATc4 knockdown markedly attenuated the IL‐1β‐induced expression of both CCL2 and CXCL10. Collectively, these results indicated that iPLA₂β plays roles in IL‐1β‐induced chemokine expression, in part via NFATc4 signaling.
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