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HIV protease inhibitor‐induced inflammatory response is coupled to ER Stress and MAPKs signaling pathways in macrophages

Macrophages are the key players in the inflammatory response. Our previous studies have shown that HIV protease inhibitors (PIs) induce ER stress and increase TNF‐¦Á and IL‐6 expression in macrophages. However, the underlying signaling mechanisms remain unclear. The aim of present study was to determine if MAPKs are involved in HIV‐PI‐induced inflammatory response in macrophages. J774A.1 cells and primary mouse peritoneal macrophages isolated from wild type and CHOP knock out mice were used in this study. Cells were treated with individual HIV PI. The mRNA and protein levels of TNF‐¦Á and IL‐6 were measured by real‐time RT‐PCR and ELISA, respectively. Activation of MAPKs was detected by Western blot using phospho‐specific antibodies. Results: HIV PIs, atazanavir and lopinavir, activated ERK1/2 and JNK, but not p38. HIV PI‐induced TNF‐¦Áand IL‐6 expression was attenuated by PD98059 and JNKII, but not SB203580. Furthermore, HIV PI‐induced ERK1/2 activation was completely inhibited by CHOP knock down using siRNA or in CHOP knock out macrophages. However, HIV PI‐induced CHOP expression was only inhibited by JNKII but not PD98059 and SB203580. Conclusions: Both ERK1/2 and JNK signaling pathways are involved in HIV PIs‐induced increase of TNF‐¦Á and IL‐6 expression in macrophages. CHOP plays an essential role in HIV PI‐induced inflammatory cytokine release by activating ERK1/2 and JNK signaling pathways in macrophages.