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Calpain inhibition induces activation of the distinct signalling pathways and cell migration in human monocytes
Author(s) -
Noma Haruyoshi,
Kato Takayuki,
Fujita Hisakazu,
Kitagawa Maki,
Yamano Tsunekazu,
Kitagawa Seiichi
Publication year - 2009
Publication title -
immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.297
H-Index - 133
eISSN - 1365-2567
pISSN - 0019-2805
DOI - 10.1111/j.1365-2567.2008.03012.x
Subject(s) - calpain , microbiology and biotechnology , mapk/erk pathway , kinase , protein kinase b , p38 mitogen activated protein kinases , monocyte , pi3k/akt/mtor pathway , signal transduction , biology , protein kinase a , cell migration , mitogen activated protein kinase , chemistry , cell , biochemistry , immunology , enzyme
Summary We have recently reported that constitutively active calpain negatively regulates activation of the distinct signalling pathways and cell migration in human neutrophils. Here, we report that a similar regulatory system is also functioning in human monocytes, but not lymphocytes. Calpain was constitutively active in resting human monocytes, but not lymphocytes. Mitogen‐activated protein kinases, including extracellular signal‐regulated kinase (ERK), p38 and c‐ Jun N‐terminal kinase (JNK), phosphatidylinositol 3‐kinase (PI3K)/Akt and p21‐activated kinase (PAK, an effector molecule of Rac) were rapidly (within 1 min) activated in monocytes, but not lymphocytes, upon exposure to calpain inhibitors (PD150606 and N ‐acetyl‐Leu‐Leu‐Nle‐CHO), but not PD145305 (the inactive analogue of PD150606). Following activation of these signalling pathways, monocytes displayed active migration within 5 min after exposure to calpain inhibitors, and active migration was sustained for more than 45 min. The micropipette method revealed that calpain inhibition‐mediated monocyte migration was chemotaxis, not random migration. The studies with pharmacological inhibitors suggest that calpain inhibition‐mediated monocyte migration is mediated by activation of ERK, p38, JNK, PI3K/Akt and Rac. NSC23766 (Rac inhibitor) and pertussis toxin (PTX) suppressed calpain inhibitor‐induced phosphorylation of distinct signalling molecules (PAK, ERK, p38, JNK and Akt) as well as cell migration, suggesting that the PTX‐sensitive G protein and Rac axis may be a possible key target of calpain inhibitors. These findings suggest that constitutively active calpain negatively regulates activation of the distinct signalling pathways and cell migration in resting monocytes, but not lymphocytes.