Published ahead of print on March 27, 2003, doi:10.1165/rcmb.2002-0158OC Am. J. Respir. Cell Mol. Biol., Volume 29, Number 3, September 2003, 367-374 A more recent version of this article appeared on September 1, 2003
Submitted on August 21, 2002 IL-4-induced apoptosis entails caspase activation and suppression of ERK phosphorylationAndrea I Doseff1*,1 Internal Medicine, Pulmonary and Critical Care and Molecular Genetics, Ohio State University, Columbus, OH, USA * To whom correspondence should be addressed. E-mail: doseff-1{at}medctr.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 (LPS), induce monocyte survival, by the inhibition of caspase-3. We hypothesized that the Th2 anti-inflammatory cytokine, 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 non-stimulated 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 (ERK) 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 ERK-dependent pathway.
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