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Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and Inflammatory Stimuli Up-Regulate Secretion of the Soluble GM-CSF Receptor in Human Monocytes: Evidence for Ectodomain Shedding of the Cell Surface GM-CSF Receptor Subunit¹

Jay M. Prevost^2,*, Jennifer L. Pelley^2,*,, Weibin Zhu^*, Gianni E. D’Egidio^*, Paul P. Beaudry, Carin Pihl^*, Graham G. Neely, Emmanuel Claret^¶, John Wijdenes^¶ and Christopher B. Brown^3,*,||

^* Cancer Biology Research Group, Southern Alberta Cancer Research Center, Departments of Biochemistry and Molecular Biology, Surgery, and Medical Science, University of Calgary, Calgary, Alberta, Canada; ^¶ Diaclone Research, Besancon, France; and ^|| Alberta Bone Marrow and Stem Cell Transplant Program

Soluble GM-CSF receptor subunit (sGMR) is a soluble isoform of the GMR that is believed to arise exclusively through alternative splicing of the GMR gene product. The sGMR mRNA is expressed in a variety of tissues, but it is not clear which cells are capable of secreting the protein. We show here that normal human monocytes, but not lymphocytes, constitutively secrete sGMR. Stimulation of monocytes with GM-CSF, LPS, PMA, or A23187 rapidly up-regulates the secretion of sGMR in a dose-dependent manner, demonstrating that secretion is also regulated. To determine whether sGMR arose exclusively through alternative splicing of the GMR gene product, or whether it could also be generated through ectodomain shedding of GMR, we engineered a murine pro-B cell line (Ba/F3) to express exclusively the cDNA for cell surface GMR (Ba/F3.GMR). The Ba/F3.GMR cell line, but not the parental Ba/F3 cell line, constitutively shed a sGMR-like protein that bound specifically to GM-CSF, was equivalent in size to recombinant alternatively spliced sGMR (60 kDa), and was recognized specifically by a mAb raised against the ectodomain of GMR. Furthermore, a broad-spectrum metalloprotease inhibitor (BB94) reduced constitutive and PMA-, A23187-, and LPS-induced secretion of sGMR by monocytes, suggesting that shedding of GMR by monocytes may be mediated in part through the activity of metalloproteases. Taken together, these observations demonstrate that sGMR is constitutively secreted by monocytes, that GM-CSF and inflammatory mediators up-regulate sGMR secretion, and that sGMR arises not only through alternative splicing but also through ectodomain shedding of cell surface GMR.

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				K. J. Garton, P. J. Gough, and E. W. Raines Emerging roles for ectodomain shedding in the regulation of inflammatory responses J. Leukoc. Biol., June 1, 2006; 79(6): 1105 - 1116. [Abstract] [Full Text] [PDF]