Fibrinogen-CD11b/CD18 interaction activates the NF-κB pathway and delays apoptosis in human neutrophils

Abstract

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 signal-regulated kinase 1/2 (ERK1/2). Since NF-κB is a key element in the regulation of apoptotic mechanisms in several immune cells, we investigated whether NF-κB is involved in the control of PMN survival by sFbg. We show that sFbg triggers inhibitor protein κB (IκB-α) degradation and NF-κB activation. Furthermore, pharmacological inhibition of NF-κB abrogates sFbg effects on apoptosis. In addition, specific inhibition of MAPK ERK1/2 significantly reduces NF-κB translocation by sFbg, suggesting a relationship between ERK1/2 and NF-κB 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-κB 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-κB regulation may be of benefit for the resolution of the inflammatory response.