Fibrinogen-CD11/CD18 interaction activates the NF-kB pathway and delays apoptosis in human neutrophils

RUBEL, C.J; GOMEZ S.A.; FERNANDEZ G.C.; ISTURIZ M.A.; CAAMAÑO, J; PALERMO M.S.

EUROPEAN JOURNAL OF IMMUNOLOGY

WILEY-VCH Verlag GmbH & Co. KgaA

Lugar: Germany ; Año: 2003 vol. 33 p. 1429 - 1438

0014-2980

The regulation of neutrophil half-life by members of the coagulation cascade is critical for the resolution of the inflammatory response. We have demonstrated that soluble fibrinogen (sFbg) delays human neutrophil (PMN) apoptosis through a mechanism that involves CD11b interactions, and phosphorylation of focal adhesion kinase (FAK) and extracellular signalregulated kinase 1/2 (ERK1/2). Since NF-KB is a key element in the regulation of apoptotic mechanisms in several immune cells, we investigated whether NF-KB is involved in the control of PMN survival by sFbg. We show that sFbg triggers inhibitor protein KB (IKB-a) degradation and NF-KB activation. Furthermore, pharmacological inhibition of NF-KB abrogates sFbg effects on apoptosis. In addition, specific inhibition of MAPK ERK1/2 significantly reduces NF-KB translocation by sFbg, suggesting a relationship between ERK1/2 and NF-KB activation. Similar results are obtained when granulocytic-differentiated HL-60 cells are treated with sFbg, making this model highly attractive for integrin-induced gene expression studies. It can be concluded that NF-KB participates in the prevention of apoptosis induced by sFbg with the participation of MAPK ERK1/2. These results shed light on the molecular mechanisms that control human granulocyte apoptosis, and suggest that NF-KB regulation may be of benefit for the resolution of the inflammatory response.