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Serum amyloid A (SAA) prevents mitochondrial dysfunction and delays constitutive neutrophil apoptosis
Author(s) -
Kebir Driss El,
Jozsef Levente,
Khreiss Tarek,
Pan Wanling,
Filep Janos G
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a13
Subject(s) - serum amyloid a , kinase , apoptosis , protein kinase b , cytochrome c , annexin , phosphatidylinositol , inflammation , mapk/erk pathway , biology , caspase 3 , microbiology and biotechnology , endocrinology , immunology , programmed cell death , biochemistry
Elevated plasma levels other acute‐phase protein SAA have been used as a marker of inflammatory diseases. We investigated whether SAA could modulate constitutive neutrophil apoptosis that is critical to the optimal expression and resolution of inflammation. Culture of human neutrophils with SAA (0.1–20 ìg/ml) markedly prolonged neutrophil longevity by delaying spontaneous apoptosis (assessed by annexin V binding and nuclear DNA content) within 24–48 h of culture. The formyl peptide receptor antagonist N‐t‐Boc‐Phe‐Leu‐Phe‐Leu‐Phe that blocks binding of SAA to its receptor (termed FPRL‐1 or ALX) almost completely abrogated the SAA effects. SAA evoked concurrent activation of the extracellular signal‐regulated kinase (ERK) and phosphatidylinositol 3‐kinase/Akt, leading to phosphorylation of BAD at Ser112 and Ser136, respectively. These led to prevention of collapse of mitochondrial transmembrane potential and mitochondrial cytochrome c release, resulting in decreased caspase‐3 activity. Consistently, pharmacological inhibition of either ERK or phosphatidylinositol 3‐kinase partially prevented these actions of SAA. Co‐treatment of neutrophils with SAA and the pan‐caspase inhibitor Z‐VAD‐FMK (20 μM) resulted in similar suppression of apoptosis than SAA or Z‐VAD‐FMK alone. Our results indicate that SAA at clinically relevant concentrations promotes neutrophil survival by suppressing the constitutively expressed apoptotic machinery, and thus may contribute to prolongation and/or amplification of the inflammatory response. (Supported by CIHR grant MOP‐64283).