Signal transduction involved in MCP-1-mediated monocytic transendothelial migration

Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant for m onocytes and T lymphocytes. The Mono-Mac6 cell line was used to examine MCP -1 receptor-mediated signal transduction events in relation to MCP-1-mediat ed monocytic transendothelial migration. MCP-1 stimulates, with distinct ti me courses, extracellular signal-related kinases (ERK1 and ERK2) and stress -activated protein kinases (SAPK1/JNK1 and SAPK2/p38), SAPK1/JNK1 activatio n was blocked by piceatannol, indicating that it is regulated by Syk kinase , whereas SAPK2/p38 activation was inhibited by PP2, revealing an upstream regulation by Src-like kinases, In contrast, ERK activation was insensitive to PP2 and piceatannol. Pertussis toxin, a blocker of Go/Gi proteins, abro gated MCP-l-induced ERK activation, but was without any effect on SAPK1/JNK 1 and SAPK2/p38 activation. These results underscore the major implication of Go/Gi proteins and nonreceptor tyrosine kinases in the early MCP-1 signa ling, Furthermore, MCP-l-mediated chemotaxis and transendothelial migration were significantly diminished by a high concentration of SB202190, a broad SAPK inhibitor, or by SB203580, a specific inhibitor of SAPK2/p38, and abo lished by pertussis toxin treatment. Altogether, these data suggest that co ordinated action of distinct signal pathways is required to produce a full response to MCP-I in terms of monocytic locomotion. (C) 2001 by The America n Society of Hematology.