Journal
BIOCHEMICAL PHARMACOLOGY
Volume 78, Issue 1, Pages 70-77Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2009.03.022
Keywords
HIV protease inhibitor; Inflammatory cytokines; ERK; ER stress; The UPR; RNA binding protein
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Funding
- NCCIH NIH HHS [R01 AT004148-01, R01 AT004148] Funding Source: Medline
- NIAID NIH HHS [R21 AI068432, R21 AI068432-02, R01 AI057189] Funding Source: Medline
- NIDDK NIH HHS [P01 DK52825, R01 DK052825, P01 DK38030, P01 DK038030] Funding Source: Medline
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HIV protease inhibitor (PI)-associated cardiovascular risk, especially atherosclerosis, has become a major concern in the clinic. Macrophages are key players in the inflammatory response and atherosclerosis formation. We have previously shown that HIV PIs induce endoplasmic reticulum (ER) stress, activate the unfolded protein response (UPR), and increase the synthesis of the inflammatory cytokines, TNF-alpha and IL-6, by regulating the intracellular translocation of RNA binding protein HuR in macrophages. However, the underlying signaling mechanisms remain unclear. We show here that the HIV PI lopinavir significantly activated the extracellular-signal regulated protein kinase (ERK), but not c-Jun N-terminal kinase (JNK) and p38 MAPK. Lopinavir-induced cytosolic translocation of HuR and TNF-alpha and IL-6 synthesis was attenuated by specific chemical inhibitor of MEK (PD98058) or over-expression of dominant negative mutant of MEK1. In addition, we demonstrated that lopinavir-induced ERK activation and TNF-alpha and IL-6 expression were completely inhibited in macrophages from CHOP null mice. Taken together, these results indicate activation of the UPR plays an essential role in HIV PI-incluced inflammatory cytokine synthesis and release by activating ERK, which increases the cytosolic translocation of HuR and subsequent binding to the 3'UTR of TNF-alpha and IL-6 mRNAs in macrophages. (c) 2009 Elsevier Inc. All rights reserved.
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