STAT-1 in macrophage apoptosis

[Guest guest]

THis is potentially of some interest.

====================================

Mol Cell Biol. 2005 Aug;25(15):6821-33. Related Articles, Links

Essential role of STAT1 in caspase-independent cell death of

activated macrophages through the p38 mitogen-activated protein

kinase/STAT1/reactive oxygen species pathway.

Kim HS, Lee MS.

Department of Medicine, Samsung Medical Center, Sungkyunkwan

University School of Medicine, 50 Irwon-dong, Kangnam-ku, Seoul 135-

710, South Korea.

Unlike other immune cells, activation of macrophages by stimulating

agents, such as lipopolysaccharide (LPS), confers significant

resistance to many apoptotic stimuli, but the underlying mechanism of

this phenomenon remains largely unknown. Here, we demonstrate that

LPS-induced early caspase activation is essential for macrophage

survival because blocking caspase activation with a pancaspase

inhibitor (zVAD [benzyloxycarbonyl-Val-Ala-Asp]) rapidly induced

death of activated macrophages. This type of death process by

zVAD/LPS was principally mediated by intracellular generation of

superoxide. STAT1 knockout macrophages demonstrated profoundly

decreased superoxide production and were resistant to treatment with

zVAD/LPS, indicating the crucial involvement of STAT1 in macrophage

death by zVAD/LPS. STAT1 level and activity were reciprocally

regulated by caspase activation and were associated with cell death.

Activation of STAT1 was critically dependent upon serine

phosphorylation induced by p38 mitogen-activated protein kinase

(MAPK) because a p38 MAPK inhibitor nullified STAT1 serine

phosphorylation, reactive oxygen species (ROS) production, and

macrophage death by zVAD/LPS. Conversely, p38 MAPK activation was

dependent upon superoxide and was also nullified in STAT1 knockout

macrophages, probably due to impaired generation of superoxide. Our

findings collectively indicate that STAT1 signaling modulates

intracellular oxidative stress in activated macrophages through a

positive-feedback mechanism involving the p38 MAPK/STAT1/ROS pathway,

which is interrupted by caspase activation. Furthermore, our study

may provide significant insights in regards to the unanticipated

critical role of STAT1 in the caspase-independent death pathway.

PMID: 16024814 [PubMed - in process]