Transforming Growth Factor-β1 Antagonizes Interleukin-5 Pro-Survival Signaling by Activating Calpain-1 in Primary Human Eosinophils
|Qifa Xie, Zhong-Jian Shen, Jiyoung Oh, Haiyan Chu and James S. Malter*|
|Department of Pathology, UT Southwestern Medical Center, Dallas, USA|
|Corresponding Author :||James S. Malter
Professor and Chair, Department of Pathology
UT Southwestern Medical Center, 5323 Harry Hines Blvd
Dallas, TX 75390-9072, USA
E-mail: [email protected]
|Received October 11, 2011; Accepted November 12, 2011; Published November 15, 2011|
|Citation: Xie Q, Shen ZJ, Oh J, Chu H, Malter JS (2011) Transforming Growth Factor-β1 Antagonizes Interleukin-5 Pro-Survival Signaling by Activating Calpain-1 in Primary Human Eosinophils. J Clin Cell Immunol S1:003. doi:10.4172/2155-9899.S1-003|
|Copyright: © 2011 Xie Q, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
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Background: Eosinophils rapidly undergo apoptosis unless exposed to prosurvival cytokines such as interleukin 5 (IL-5) or granulocyte-macrophage colony stimulating factor (GM-CSF). In vivo, eosinophils are exposed to TGF-β 1 which can induce apoptosis suggesting it may function to counteract the effects of IL-5 or GM-CSF and limit, in vivo tissue eosinophilia.
Objective: The objective of this study was to investigate the proapoptotic effects of TGF-β alone and in combination with IL-5 on eosinophils.
Methods: Peripheral blood eosinophil (PBEos) viability was assessed using flow cytometry after exposure to TGF-β1 and IL-5. Calpain-1 activation was determined in cell extracts by western blot analysis of endogenous substrates and with a fluorogenic α-spectrin substrate. Molecular interactions between calpain1 and calpastatin were assessed by immunoprecipitation and western blotting.
Results: Physiologic concentrations of TGF-β1 significantly antagonized the prosurvival effects of IL-5. TGF-β1- induced apoptosis was suppressed by inhibitors of calpain, or its downstream target, caspase 3. TGF-β1 signaling through Smad3 was unaffected by IL-5 and was required for the pro-apoptotic effects of TGF-β1. However, IL-5 induced Akt phosphorylation was inhibited by TGF-β1 and was associated with accelerated calpain cleavage and eosinophil death.
Conclusion: TGF-β1 induces calpain-1 activation through antagonism of Akt which induces caspase activation and eosinophil apoptosis.