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.
