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Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways

Da Costa, Ana
Bianchi, Giordano
Bertolotto, Maria
Dallegri, Franco
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Published in Cellular signalling. 2008, vol. 20, no. 3, p. 557-68
Abstract Strong evidence suggests that neutrophils may play an active role in acute and chronic inflammatory disorders, such as rheumatoid arthritis and atherosclerosis. Given the role of pro-inflammatory cytokine TNF-alpha in these inflammatory processes, we planned the present study to investigate the effect of short term incubation with TNF-alpha on neutrophil migration to CCL3, a chemokine produced in inflammatory sites and normally devoid of neutrophil chemotactic properties. We found that TNF-alpha primed neutrophils for migration to CCL3 via CCR5. TNF-alpha-induced migration was a consequence of the TNF-alpha-induced up-regulation of integrin CD11b/CD18 (Mac-1) on neutrophil surface. Furthermore, TNF-alpha activity was found to be strictly dependent on the activation of ERK 1/2 p44, cooperating with the intracellular pathways involving Src kinases, PI3K/Akt, p38 MAPK, well known as activated in response to classical chemoattractants (CXCL8) or priming agents (GM-CSF). On the contrary, the effect of TNF-alpha on neutrophil migration to CCL3 was not dependent on JNK 1/2. In conclusion, the present report shows that TNF-alpha unveils a previously unknown capacity of neutrophils to migrate to CCL3 through the intervention of Mac-1. TNF-alpha regulates Mac-1 up-regulation through signalling pathways, involving various kinases, but not JNK 1/2. Although highly speculative, ERK 1/2 p44 may represent a selective target for the pharmacologic manipulation of neutrophil-mediated adverse activities in TNF-alpha-mediated inflammatory states.
Keywords 1-Phosphatidylinositol 3-Kinase/metabolismAdultAntigens, CD11b/metabolismAntigens, CD18/metabolismChemokine CCL3/metabolismChemotaxis, LeukocyteHumansInflammation/immunology/metabolismMacrophage-1 Antigen/metabolismMiddle AgedMitogen-Activated Protein Kinase 1/metabolismMitogen-Activated Protein Kinase 3/metabolismNeutrophil ActivationNeutrophils/enzymology/immunology/metabolismProto-Oncogene Proteins c-akt/metabolismReceptors, CCR5/metabolismRecombinant Proteins/metabolismSignal TransductionTumor Necrosis Factor-alpha/metabolismUp-RegulationP38 Mitogen-Activated Protein Kinases/metabolismSrc-Family Kinases/metabolism
PMID: 18164590
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MONTECUCCO, Fabrizio et al. Tumor necrosis factor-alpha (TNF-alpha) induces integrin CD11b/CD18 (Mac-1) up-regulation and migration to the CC chemokine CCL3 (MIP-1alpha) on human neutrophils through defined signalling pathways. In: Cellular signalling, 2008, vol. 20, n° 3, p. 557-68. doi: 10.1016/j.cellsig.2007.11.008 https://archive-ouverte.unige.ch/unige:2143

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Deposited on : 2009-06-23

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