Fibrinogen-CD11b/CD18 interaction activates the NF-kappa B pathway and delays apoptosis in human neutrophils.
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-kappa B is a key element in the regulation of apoptotic mechanisms in several immune cells, we investigated whether NF-kappa B is involved in the control of PMN survival by sFbg. We show that sFbg triggers inhibitor protein kappa B (I kappa B-alpha) degradation and NF-kappa B activation. Furthermore, pharmacological inhibition of NF-kappa B abrogates sFbg effects on apoptosis. In addition, specific inhibition of MAPK ERK1/2 significantly reduces NF-kappa B translocation by sFbg, suggesting a relationship between ERK1/2 and NF-kappa B 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-kappa B 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-kappa B regulation may be of benefit for the resolution of the inflammatory response.
División Inmunología, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina. rubel@sinectis.com.ar
Carolina
C
Rubel
Sonia
S
Gómez
Gabriela C
GC
Fernández
Martín A
MA
Isturiz
Jorge
J
Caamaño
Marina S
MS
Palermo
D017209:Apoptosis / Q000502:physiology*; D039481:CD11b Antigen / Q000502:physiology*; D018821:CD18 Antigens / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D005340:Fibrinogen / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D016328:NF-kappa B / Q000502:physiology*; D009504:Neutrophils / Q000502:physiology*; D021381:Protein Transport; D019061:src-Family Kinases / Q000502:physiology
D039481:CD11b Antigen; D018821:CD18 Antigens; D016328:NF-kappa B; D005340:Fibrinogen; D019061:src-Family Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases