4.5 Article

Identification and Characterization of Poly(I:C)-induced Molecular Responses Attenuated by Nicotine in Mouse Macrophages

Journal

MOLECULAR PHARMACOLOGY
Volume 83, Issue 1, Pages 61-72

Publisher

AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.112.081497

Keywords

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Funding

  1. National Institutes of Health National Institute on Drug Abuse [R01DA013783, R01DA016149, R01DA026356]
  2. National Natural Science Foundation of China [81273223]
  3. China Scholarship Council

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To further our understanding of the effects of nicotine on the molecular responses of macrophages during virus or virus-like infections, poly(I:C)-stimulated macrophage-like RAW264.2 cells or mouse primary peritoneal macrophages were challenged with nicotine; and their molecular responses were evaluated using a qRT-PCR array, antibody array, ELISA, Western blotting, and Ca2+ imaging. Of 51 genes expressed in the Toll-like receptor (TLR) and RIG-I-like receptor (RLR) pathways, mRNA expression of 15 genes in RAW264.7 cells was attenuated by nicotine, of which mRNA expression of IL-6, TNF-alpha, and IL-1 beta was confirmed to be attenuated in peritoneal macrophages. Concurrently, nicotine treatment attenuated the release of IL-6 and TNF-alpha from poly (I: C)-stimulated macrophages. However, when poly(I:C)-stimulated macrophages were challenged with nicotine plus a-bungarotoxin (alpha-BTX), secretion of IL-6 and TNF-alpha was found to be in a level seen with poly(I:C) stimulation only, indicating that alpha 7-nAChR, a highly Ca2+ permeable ion channel sensitive to blockade by alpha-BTX, is involved in this process. Furthermore, results from an antibody array indicated that nicotine treatment attenuated the phosphorylation of 82 sites, including Thr286 on CaMKII alpha, from poly(I:C)-stimulated RAW264.7 cells, of which 28 are expressed in the downstream cascade of Ca2+ signaling. Coincidentally, poly(I:C)-stimulated macrophages showed attenuated expression of phosphorylated CaMKII alpha when pretreated with nicotine. In addition, nicotine attenuated intracellular Ca2+ signal from poly(I:C)-stimulated RAW264.7 cells. Collectively, these results indicate that poly (I:C)-induced molecular responses of macrophages could be significantly attenuated by nicotine.

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