Abstract
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.
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Project supported by the Major National Basic Research Program of China (No G2000056908) and a grant from the National Natural Science Foundation of China (No 30330250) awarded to Prof. Xian Wang as well as a grant from NIH (No GM 50401) awarded to Prof. Daniel G Remick.
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Zeng, Xk., Guan, Yf., Remick, D. et al. Signal pathways underlying homocysteine-induced production of MCP-1 and IL-8 in cultured human whole blood. Acta Pharmacol Sin 26, 85–91 (2005). https://doi.org/10.1111/j.1745-7254.2005.00005.x
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DOI: https://doi.org/10.1111/j.1745-7254.2005.00005.x
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