This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Alblas, J.
Right arrow Articles by van den Berg, T. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Alblas, J.
Right arrow Articles by van den Berg, T. K.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, August 2005, p. 7181-7192, Vol. 25, No. 16
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.16.7181-7192.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Signal Regulatory Protein {alpha} Ligation Induces Macrophage Nitric Oxide Production through JAK/STAT- and Phosphatidylinositol 3-Kinase/Rac1/NAPDH Oxidase/H2O2-Dependent Pathways{dagger}

Jacqueline Alblas,1,{ddagger} Henk Honing,1,{ddagger} Chantal Renardel de Lavalette,1 Marion H. Brown,2 Christine D. Dijkstra,1 and Timo K. van den Berg1*

Department of Molecular Cell Biology and Immunology, Vrije University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands,1 Sir William Dunn School of Pathology, South Parks Road, Oxford, United Kingdom2

Received 19 October 2004/ Returned for modification 26 November 2004/ Accepted 3 May 2005

Signal regulatory protein {alpha} (SIRP{alpha}) is a glycoprotein receptor that recruits and signals via the tyrosine phosphatases SHP-1 and SHP-2. In macrophages SIRP{alpha} can negatively regulate the phagocytosis of host cells and the production of tumor necrosis factor alpha. Here we provide evidence that SIRP{alpha} can also stimulate macrophage activities, in particular the production of nitric oxide (NO) and reactive oxygen species. Ligation of SIRP{alpha} by antibodies or soluble CD47 triggers inducible nitric oxide synthase expression and production of NO. This was not caused by blocking negative-regulatory SIRP{alpha}-CD47 interactions. SIRP{alpha}-induced NO production was prevented by inhibition of the tyrosine kinase JAK2. JAK2 was found to associate with SIRP{alpha} in macrophages, particularly after SIRP{alpha} ligation, and SIRP{alpha} stimulation resulted in JAK2 and STAT1 tyrosine phosphorylation. Furthermore, SIRP{alpha}-induced NO production required the generation of hydrogen peroxide (H2O2) by a NADPH oxidase (NOX) and the phosphatidylinositol 3-kinase (PI3-K)-dependent activation of Rac1, an intrinsic NOX component. Finally, SIRP{alpha} ligation promoted SHP-1 and SHP-2 recruitment, which was both JAK2 and PI3-K dependent. These findings demonstrate that SIRP{alpha} ligation induces macrophage NO production through the cooperative action of JAK/STAT and PI3-K/Rac1/NOX/H2O2 signaling pathways. Therefore, we propose that SIRP{alpha} is able to function as an activating receptor.

* Corresponding author. Mailing address: Department of Molecular Cell Biology and Immunology, VU Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Phone: 31.20.4448058. Fax: 31.20.4448081. E-mail: t.vandenberg{at}vumc.nl.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

Molecular and Cellular Biology, August 2005, p. 7181-7192, Vol. 25, No. 16
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.16.7181-7192.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Schroder, K., Kohnen, A., Aicher, A., Liehn, E. A., Buchse, T., Stein, S., Weber, C., Dimmeler, S., Brandes, R. P. (2009). NADPH Oxidase Nox2 Is Required for Hypoxia-Induced Mobilization of Endothelial Progenitor Cells. Circ. Res. 105: 537-544 [Abstract] [Full Text]  
  • Munitz, A., McBride, M. L., Bernstein, J. S., Rothenberg, M. E. (2008). A dual activation and inhibition role for the paired immunoglobulin-like receptor B in eosinophils. Blood 111: 5694-5703 [Abstract] [Full Text]  
  • Kong, X.-N., Yan, H.-X., Chen, L., Dong, L.-W., Yang, W., Liu, Q., Yu, L.-X., Huang, D.-D., Liu, S.-Q., Liu, H., Wu, M.-C., Wang, H.-Y. (2007). LPS-induced down-regulation of signal regulatory protein {alpha} contributes to innate immune activation in macrophages. JEM 204: 2719-2731 [Abstract] [Full Text]  
  • Tomizawa, T., Kaneko, Y., Kaneko, Y., Saito, Y., Ohnishi, H., Okajo, J., Okuzawa, C., Ishikawa-Sekigami, T., Murata, Y., Okazawa, H., Okamoto, K., Nojima, Y., Matozaki, T. (2007). Resistance to Experimental Autoimmune Encephalomyelitis and Impaired T Cell Priming by Dendritic Cells in Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 Mutant Mice. J. Immunol. 179: 869-877 [Abstract] [Full Text]  
  • Okajo, J., Kaneko, Y., Murata, Y., Tomizawa, T., Okuzawa, C., Saito, Y., Kaneko, Y., Ishikawa-Sekigami, T., Okazawa, H., Ohnishi, H., Matozaki, T., Nojima, Y. (2007). Regulation by Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate-1 of {alpha}-Galactosylceramide-Induced Antimetastatic Activity and Th1 and Th2 Responses of NKT Cells. J. Immunol. 178: 6164-6172 [Abstract] [Full Text]  
  • van Beek, E. M., Cochrane, F., Barclay, A. N., van den Berg, T. K. (2005). Signal Regulatory Proteins in the Immune System. J. Immunol. 175: 7781-7787 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»