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Substance P Enhances Chemokine Expression in Murine Macrophages via ERK/p38 MAPK‐NF‐κB Pathways
Author(s) -
Jia Sun,
Ramnath Raina,
Bhatia Madhav
Publication year - 2008
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/fasebj.22.1_supplement.1070.17
Subject(s) - transactivation , chemokine , mapk/erk pathway , p38 mitogen activated protein kinases , microbiology and biotechnology , ccl21 , chemokine receptor , nf κb , chemistry , cxcl2 , xcl2 , biology , transcription factor , signal transduction , cancer research , receptor , biochemistry , gene
In the current study, we aim to investigate the role of substance P (SP) in enhancing the inflammatory chemokine response of macrophages. Using the murine macrophage cell line RAW 264.7 as well as isolated primary macrophages, we show that SP (10 nM) elicits selective chemokine production from macrophages. MIP‐2 and MCP‐1 are two major chemokines synthesized by macrophages in response to SP. Moreover, SP strongly induces the classical pathway of I B‐dependent NF‐κB activation and enhances DNA‐binding as well as transactivation activity of the transcription factor. SP‐evoked transcriptional induction of chemokines is neurokinin‐1 receptor‐specific. Furthermore, SP stimulation of macrophages activates the ERK1/2 and p38 MAPK. Blockade of the two MAPK pathways with specific inhibitors abolishes SP‐elicited NF‐κB‐driven chemokine production. The attenuation of NF‐κB response by ERK1/2 inhibitor does not involve impairment of DNA binding of the transcription factor but correlates with diminished Ser276‐phosphorylated status and transactivation potential of the p65 subunit. The p38 MAPK controls NF‐κB‐responsive chemokine expression by regulating both the DNA binding and transactivation activity of the transcription factor. Collectively, our data demonstrate that SP enhances selective inflammatory chemokine production by murine macrophages via ERK/p38 MAPK‐mediated NF‐κB activation.