title: 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.
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.
authors.affiliation: Laboratory of Phagocyte Physiopathology, First Clinic of Internal Medicine, Department of Internal Medicine and Medical Specialties, University of Genoa Medical School, Genoa, Italy. fabrizio.montecucco@medecine.unige.ch
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Montecucco
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Ana
authors.initials: A
authors.lastname: Da Costa
authors.forename: Giordano
authors.initials: G
authors.lastname: Bianchi
authors.forename: Maria
authors.initials: M
authors.lastname: Bertolotto
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Franco
authors.initials: F
authors.lastname: Dallegri
authors.forename: Luciano
authors.initials: L
authors.lastname: Ottonello
mesh_terms: D000328:Adult; D039481:CD11b Antigen / Q000378:metabolism*; D018821:CD18 Antigens / Q000378:metabolism*; D054405:Chemokine CCL3 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018375:Neutrophil Activation; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: C515429:CCL3 protein, human; D039481:CD11b Antigen; D018821:CD18 Antigens; D054405:Chemokine CCL3; C509295:ITGAM protein, human; D016177:Macrophage-1 Antigen; D019713:Receptors, CCR5; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases