Insulin primes human neutrophils for CCL3-induced migration: crucial role for JNK 1/2.
The present article shows that a short-term exposure of purified human neutrophils to recombinant insulin conferred on these cells both the ability to migrate and the capacity to mobilize [Ca2+]i in response to CCL3, a chemokine per se ineffective with native neutrophils. Furthermore, the effects of recombinant insulin were reproduced by short-term incubation with sera from adult patients with metabolic syndrome, known to be characterized by a hyperinsulinemic state. A strict linear correlation (P<0.01) between sera insulin levels and sera's ability to induce neutrophil locomotion was indeed found. Our data also suggest that (i) insulin primed neutrophils for migration to CCL3 via the selective activation of JNK 1/2, as shown by the use of inhibitors and kinase activation assay; (ii) the activation of Src kinases was necessary but not sufficient for CCL3-induced locomotory activity; (iii) PI3K-Akt, ERK 1/2, and p38 MAPK were not involved in insulin-induced migratory competence. In summary, we provided evidence that the exposition of neutrophils to insulin, as it occurs in hyperinsulinemic conditions, confers the competence of the cells to migrate in response to CCL3, known to be generated near atherosclerotic plaques. As neutrophils have been recently suggested to be involved in breaking unstable atherosclerotic plaques, the present findings contribute to the understanding of the pathophysiology of plaque instability. Finally, biochemical analysis herein carried out raises the hypothesis of JNK 1/2 as an attractive therapeutic target.
Montecucco
Fabrizio
F
Clinic of Internal Medicine I, Department of Internal Medicine, University of Genoa, Medical School, Italy.
Bianchi
Giordano
G
Bertolotto
Maria
M
Viviani
Giorgio
G
Dallegri
Franco
F
Ottonello
Luciano
L
D000328:Adult; D000368:Aged; D002465:Cell Movement / Q000502:physiology*; D054405:Chemokine CCL3; D019742:Chemokines, CC / Q000502:physiology*; D004789:Enzyme Activation; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D008875:Middle Aged; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism
C515429:CCL3 protein, human; D054405:Chemokine CCL3; D019742:Chemokines, CC; D007328:Insulin; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8