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Role of protein kinase C and phosphoinositide 3‐kinase‐Akt in substance P‐induced proinflammatory pathways in mouse macrophages
Author(s) -
Sun Jia,
Ramnath Raina Devi,
Tamizhselvi Ramasamy,
Bhatia Madhav
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-121756
Subject(s) - protein kinase b , pi3k/akt/mtor pathway , microbiology and biotechnology , proinflammatory cytokine , chemokine , signal transduction , chemistry , kinase , protein kinase c , phosphoinositide 3 kinase , biology , inflammation , immunology
Neuropeptide modulation of immune cell function is an important mechanism of neuroimmune intersystem crosstalk. Substance P (SP) is one such key neuropeptide involved. In this study, we investigated the yet unexplored cellular mechanisms of SP‐mediated inflammatory responses in macrophages using a mouse macrophage‐like cell line RAW 264.7 and isolated peritoneal macrophages. We found that the conventional PKCα and novel PKCδ and ε were selectively activated by SP via its primary neurokinin‐1 receptor (NK‐1R) on the cells. Activation of these PKC isoforms mediated the activation of downstream extracellular signal‐regulated kinase‐1/2 (ERK1/2) and the transcription factor NF‐κB, which drove the transcription of inducible chemokines in macrophages. Additionally, phosphoinositide 3‐kinase (PI3K)‐Akt was also activated by SP/NK‐1R in macrophages. Inhibition of PI3K‐Akt pathway attenuated ERK1/2 and NF‐κB activation, suggesting it also played a part in SP‐induced cellular inflammatory response. Kinetic analysis indicated that PKC isoforms induced early ERK1/2 activation, while PI3K‐Akt contributed to the pathway at later time points. It was further demonstrated that PKC and PI3K‐Akt were activated independent of each other. Collectively, our results suggest that SP/NK‐1R activates two convergent proinflammatory signaling pathways, PKCs and PI3K‐Akt, resulting in ERK1/2 and NF‐κB activation and chemokine production in mouse macrophages.—Sun, J., Ramnath, R. D., Tamizhselvi, R., Bhatia, M. Role of protein kinase C and phosphoinositide 3‐kinase‐Akt in substance P‐induced proinflammatory pathways in mouse macrophages. FASEB J . 23, 997–1010 (2009)