PMID- 18164590 OWN - NLM STAT- MEDLINE DCOM- 20080327 LR - 20171116 IS - 0898-6568 (Print) IS - 0898-6568 (Linking) VI - 20 IP - 3 DP - 2008 Mar TI - 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. PG - 557-68 LID - 10.1016/j.cellsig.2007.11.008 [doi] AB - 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. FAU - Montecucco, Fabrizio AU - Montecucco F AD - 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 FAU - Steffens, Sabine AU - Steffens S FAU - Burger, Fabienne AU - Burger F FAU - Da Costa, Ana AU - Da Costa A FAU - Bianchi, Giordano AU - Bianchi G FAU - Bertolotto, Maria AU - Bertolotto M FAU - Mach, Francois AU - Mach F FAU - Dallegri, Franco AU - Dallegri F FAU - Ottonello, Luciano AU - Ottonello L LA - eng PT - Journal Article DEP - 20071126 PL - England TA - Cell Signal JT - Cellular signalling JID - 8904683 RN - 0 (CCL3 protein, human) RN - 0 (CD11b Antigen) RN - 0 (CD18 Antigens) RN - 0 (Chemokine CCL3) RN - 0 (ITGAM protein, human) RN - 0 (Macrophage-1 Antigen) RN - 0 (Receptors, CCR5) RN - 0 (Recombinant Proteins) RN - 0 (Tumor Necrosis Factor-alpha) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.10.2 (src-Family Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) SB - IM MH - Adult MH - CD11b Antigen/*metabolism MH - CD18 Antigens/*metabolism MH - Chemokine CCL3/*metabolism MH - *Chemotaxis, Leukocyte MH - Humans MH - Inflammation/immunology/metabolism MH - Macrophage-1 Antigen/*metabolism MH - Middle Aged MH - Mitogen-Activated Protein Kinase 1/metabolism MH - Mitogen-Activated Protein Kinase 3/metabolism MH - Neutrophil Activation MH - Neutrophils/enzymology/immunology/*metabolism MH - Phosphatidylinositol 3-Kinases/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Receptors, CCR5/metabolism MH - Recombinant Proteins/metabolism MH - *Signal Transduction MH - Tumor Necrosis Factor-alpha/*metabolism MH - Up-Regulation MH - p38 Mitogen-Activated Protein Kinases/metabolism MH - src-Family Kinases/metabolism EDAT- 2008/01/01 09:00 MHDA- 2008/03/28 09:00 CRDT- 2008/01/01 09:00 PHST- 2007/10/12 00:00 [received] PHST- 2007/11/15 00:00 [revised] PHST- 2007/11/16 00:00 [accepted] PHST- 2008/01/01 09:00 [pubmed] PHST- 2008/03/28 09:00 [medline] PHST- 2008/01/01 09:00 [entrez] AID - S0898-6568(07)00364-6 [pii] AID - 10.1016/j.cellsig.2007.11.008 [doi] PST - ppublish SO - Cell Signal. 2008 Mar;20(3):557-68. doi: 10.1016/j.cellsig.2007.11.008. Epub 2007 Nov 26.