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Pentoxifylline attenuates fMLP‐induced oxidative burst in human neutrophils through PKA dependent and independent mechanisms: Effect on Ras, Raf, and MAPK activation
Author(s) -
Deree Jessica,
Costantini Todd,
Woon Tiffany,
Loomis William H,
Coimbra Raul
Publication year - 2008
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.22.1_supplement.166.8
Subject(s) - respiratory burst , p38 mitogen activated protein kinases , mapk/erk pathway , pentoxifylline , protein kinase a , oxidative phosphorylation , phosphorylation , kinase , chemistry , western blot , microbiology and biotechnology , biology , pharmacology , biochemistry , gene
Pentoxifylline (PTX) has been proven to be an inhibitor of fMLP‐induced neutrophil (PMN) oxidative burst and is thought to function by increasing cAMP and Protein kinase A (PKA). We hypothesized that PTX diminishes production of the respiratory burst by both PKA dependent and independent mechanisms. Human PMNs (1 x 10 6 cells/sample) were isolated and stimulated with fMLP (1μmol/L) and PTX. PMN activation was determined by the cytochrome C reduction method in the presence and absence of p38 MAPK (SB203580 10 mM), ERK 1/2 (PD98059 50 mM), and PKA inhibitors (H89 10 mM). Western blot analysis of Ras, c‐Raf, p38 MAPK, and ERK 1/2 was performed in PMNs exposed to fMLP and PTX. PTX produced a decrease in the reduction of cytochrome C that was diminished but not abrogated by H89 exposure. The reduction in Ras activation seen with PTX was not effected by the presence of H89. The attenuation in phosphorylation of c‐Raf p38 MAPK, and ERK 1/2 observed with PTX was only partially reversed with H89. PTX attenuates fMLP induction of oxidative burst through effects on Ras, c‐Raf, p38 MAPK, and ERK 1/2. The attenuation of early events by PTX in the cascade leading to production of the oxidative burst is PKA independent, while the effects of PTX on signaling distal to c‐Raf phosphorylation rely on both PKA‐dependent and independent mechanisms. Source of Support: Department of Surgery, University of California San Diego