Published ahead of print on March 27, 2003, doi:10.1165/rcmb.2002-0158OC
© 2003 American Thoracic Society DOI: 10.1165/rcmb.2002-0158OC Interleukin-4–Induced Apoptosis Entails Caspase Activation and Suppression of Extracellular Signal–Regulated Kinase PhosphorylationThe Dorothy M. Davis Heart and Lung Research Institute, and Divisions of Pulmonary and Critical Care and Molecular Genetics, Ohio State University, Columbus, Ohio Address correspondence to: A. I. Doseff, 201 Davis Heart and Lung Research Institute, Molecular Genetics, Ohio State University, 473 West 12th, Columbus, OH 43210. E-mail: doseff-1{at}medctr.osu.edu or wewers.2{at}osu.edu Monocytes are important components of the innate immune response. The number of circulating monocytes is controlled in part by apoptosis. We have previously shown that monocyte apoptosis requires the activation of caspase-3, a central component of the apoptotic machinery, and that several stimulatory signals, including endotoxin (lipopolysaccharide [LPS]), induce monocyte survival, by the inhibition of caspase-3. We hypothesized that the Th2 anti-inflammatory cytokine, interleukin (IL)-4, may also influence monocyte life span by modulating the apoptotic cascade and the kinases known to be activated by LPS. Here, we show that the IL-4–dependent killing of LPS-treated monocytes reactivates the apoptotic cascade blocked by endotoxin, evidenced by the activity of the effector caspase-3 and the upstream caspases-8 and -9. IL-4 did not affect the activity of caspase-3 or the fragmentation of DNA in nonstimulated monocytes, suggesting that the induction of the apoptotic cascade by IL-4 is specific for stimulated monocytes. In addition, we show that the ability of IL-4 to induce apoptosis is associated with the dephosphorylation of the extracellular signal–regulated kinase, but not with changes in TLR4 expression. Together, these findings suggest a molecular mechanism by which the anti-inflammatory cytokine IL-4 modulates the life span of monocytes at least in part by an extracellular signal–regulated kinase–dependent pathway.
Abbreviations: aminotrifluoromethylcoumarin assay, afc • dimethyl sulfoxide, DMSO • extracellular signal–regulated kinase, ERK • interleukin, IL • lipopolysaccharide, LPS • mitogen-activated protein kinase, MAPK • phosphate-buffered saline, PBS • phycoerythrin, PE This article has been cited by other articles:
|
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
