Open AccessSignal pathways underlying homocysteine‐induced production of MCP‐1 and IL‐8 in cultured human whole blood
Author(s) -
ZENG Xiaokun,
GUAN Youfei,
REMICK Daniel G,
WANG Xian
Publication year - 2005
Publication title -
acta pharmacologica sinica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.514
H-Index - 90
eISSN - 1745-7254
pISSN - 1671-4083
DOI - 10.1111/j.1745-7254.2005.00005.x
Subject(s) - calphostin c , protein kinase c , chemokine , mapk/erk pathway , signal transduction , calphostin , protein kinase a , chemistry , microbiology and biotechnology , mitogen activated protein kinase , p38 mitogen activated protein kinases , kinase , biochemistry , endocrinology , biology , medicine , receptor
Aim: To elucidate the mechanisms underlying homocysteine (Hcy)‐induced chemokine production. Methods: Human whole blood was pretreated with inhibitors of calmodulin (CaM), protein kinase C (PKC), protein tyrosine kinase (PTK), mitogen‐activated protein kinase (MAPK), and NF‐κB and activators of PPARγ for 60 min followed by incubation with Hcy 100 μmol/L for 32 h. The levels of mitogen chemokine protein (MCP)‐1 and interleukin‐8 (IL‐8) were determined by enzyme‐linked immunosorbant assay (ELISA). Results: Inhibitors of PKC (calphostin C, 50‐500 nmol/L and RO‐31‐8220, 10–100 nmol/L), CaM (W7, 28–280 μmol/L), ERK1/2 MAPK (PD 98059, 2–20 μmol/L), p38 MAPK (SB 203580, 0.6–6 μmol/L), JNK MAPK (curcumin, 2–10 μmol/L), and NF‐κB (PDTC, 10‐100 nmol/L) markedly reduced Hcy 100 μmol/L‐induced production of MCP‐1 and IL‐8 in human cultured whole blood, but the inhibitors of PTK (genistein, 2.6–26 μmol/L and tyrphostin, 0.5‐5 μmol/L) had no obvious effect on MCP‐1 and IL‐8 production. PPARγ activators (ciglitazone 30 μmol/L and troglitazone 10 μmol/L) depressed the Hcy‐induced MCP‐1 production but not IL‐8 production in the cultured whole blood. Conclusion: Hcy‐induced MCP‐1 and IL‐8 production is mediated by activated signaling pathways such as PKC, CaM, MAPK, and NF‐κB. Our results not only provide clues for the signal transduction pathways mediating Hcy‐induced chemokine production, but also offer a plausible explanation for a pathogenic role of hyperhomocysteinemia in these diseases.