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* Department of Biochemistry and Molecular Biology,
Sealy Center for Molecular Medicine, and
University of Texas Medical Branch National Heart, Lung, and Blood Institute Proteomics Center, University of Texas Medical Branch, Galveston, TX 77555
Reversal of eosinophilic inflammation has been an elusive therapeutic goal in the management of asthma pathogenesis. In this regard, GM-CSF is a primary candidate cytokine regulating eosinophil activation and survival in the lung; however, its molecular mechanism of propagation and maintenance of stimulated eosinophil activation is not well understood. In this study, we elucidate those late interactions occurring between the GM-CSF receptor and activated eosinophil signaling molecules. Using coimmunoprecipitation with GM-CSF-stimulated eosinophils, we have identified that the GM-CSF receptor β-chain (GMRβ) interacted with ICAM-1 and Shp2 phosphatase, as well as Slp76 and ADAP adaptor proteins. Separate experiments using affinity binding with a tyrosine-phosphorylated peptide containing an ITIM (ICAM-1 residues 480–488) showed binding to Shp2 phosphatase and GMRβ. However, the interaction of GMRβ with the phosphorylated ICAM-1-derived peptide was observed only with stimulated eosinophil lysates, suggesting that the interaction of GMRβ with ICAM-1 required phosphorylated Shp2 and/or phosphorylated GMRβ. Importantly, we found that inhibition of ICAM-1 in activated eosinophils blocked GM-CSF-induced expression of c-fos, c-myc, IL-8, and TNF-
. Moreover, inhibition of ICAM-1 expression with either antisense oligonucleotide or an ICAM-1-blocking Ab effectively inhibited ERK activation and eosinophil survival. We concluded that the interaction between ICAM-1 and the GM-CSF receptor was essential for GM-CSF-induced eosinophil activation and survival. Taken together, these results provide novel mechanistic insights defining the interaction between ICAM-1 and the GM-CSF receptor and highlight the importance of targeting ICAM-1 and GM-CSF/IL-5/IL-3 receptor systems as a therapeutic strategy to counter eosinophilia in asthma.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute’s Proteomics Initiative NO1HV-28184 (to A.K.), National Institutes of Health Grants 1R24 CA88317 (to A.K.) and PO1 AI062885 (to A.B.).
2 Address correspondence and reprint requests to Dr. Alexander Kurosky, Department of Biochemistry and Molecular Biology, 301 University Boulevard, University of Texas Medical Branch, Galveston, TX 77555. E-mail address: akurosky{at}utmb.edu
3 Abbreviations used in this paper: EPO, eosinophil peroxidase; GMR, GM-CSF receptor -chain; GMRβ, GM-CSF receptor β-chain; RT, room temperature; 7-AAD, 7-aminactinomycin D; DSP, dithio-bis(succinimydl)propionate; ODN, oligodeoxynucleotide.
This article has been cited by other articles:
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  V. Starosta, K. Pazdrak, I. Boldogh, T. Svider, and A. Kurosky Lipoxin A4 Counterregulates GM-CSF Signaling in Eosinophilic Granulocytes J. Immunol., December 15, 2008; 181(12): 8688 - 8699. [Abstract] [Full Text] [PDF]
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