The Journal of Immunology, Vol 156, Issue 7 2522-2527, Copyright © 1996 by American Association of Immunologists

ARTICLES

Effects of granulocyte-macrophage colony-stimulating factor on eicosanoid production by mononuclear phagocytes

TG Brock, RW McNish, MJ Coffey, TC Ojo, SM Phare and M Peters-Golden
Department of Internal Medicine, University of Michigan, Ann Arbor, 48109, USA.

Granulocyte-macrophage CSF (GM-CSF) primes granulocytes for leukotriene (LT) synthesis. Here, we examined the effects of GM-CSF on arachidonic acid (AA) metabolism in rat alveolar macrophages (AM), peritoneal macrophages, and human peripheral blood monocytes. Pretreatment of AMs with GM-CSF for 24 h significantly increased the synthesis of immunoreactive LTB4 upon subsequent stimulation with calcium ionophore. Enhanced LT synthesis required a minimum of 6 h of GM-CSF pretreatment, suggesting that protein synthesis was required for enhanced LT production; indeed, cycloheximide completely abolished the GM-CSF effect on LT synthesis. HPLC analysis confirmed that GM-CSF primed AMs for enhanced generation of LTB4, as well as the 5-lipoxygenase products LTC, and 5-HETE. Moreover, parallel increases in other AA metabolites and free AA were observed following GM-CSF pretreatment. The enhanced production of all AA metabolites indicated that GM-CSF up-regulated AA release. Consistent with this, whole cell lysates from GM-CSF-treated AMs demonstrated increased phospholipase A2 (PLA2) activity. The increased activity was resistant to DTT, indicating the involvement of a PLA2 other than the 14-kDa PLA2s. By immunoblot analysis, GM-CSF treatment caused an increase in the 85-kDa PLA2 protein comparable to the observed increase in PLA2 activity. Unlike AMs, neither peritoneal macrophages nor peripheral blood monocytes showed increased eicosanoid generation or increased expression of the 85-kDa PLA2 protein following GM-CSF pretreatment. These results indicate that GM-CSF increases the capacity of AMs, but not peritoneal macrophages or peripheral blood monocytes, to generate eicosanoids. This effect results from increased PLA2 activity, due at least in part to increased levels of the 85-kDa PLA2 protein.

This article has been cited by other articles:

				M. N. Ballinger, L. L. N. Hubbard, T. R. McMillan, G. B. Toews, M. Peters-Golden, R. Paine III, and B. B. Moore Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L114 - L122. [Abstract] [Full Text] [PDF]

				M. N. Ballinger, R. Paine III, C. H. C. Serezani, D. M. Aronoff, E. S. Choi, T. J. Standiford, G. B. Toews, and B. B. Moore Role of Granulocyte Macrophage Colony-Stimulating Factor during Gram-Negative Lung Infection with Pseudomonas aeruginosa Am. J. Respir. Cell Mol. Biol., June 1, 2006; 34(6): 766 - 774. [Abstract] [Full Text] [PDF]

				L. A. Spencer, R. C. N. Melo, S. A. C. Perez, S. P. Bafford, A. M. Dvorak, and P. F. Weller Cytokine receptor-mediated trafficking of preformed IL-4 in eosinophils identifies an innate immune mechanism of cytokine secretion PNAS, February 28, 2006; 103(9): 3333 - 3338. [Abstract] [Full Text] [PDF]

				M. Peters-Golden, C. Canetti, P. Mancuso, and M. J. Coffey Leukotrienes: Underappreciated Mediators of Innate Immune Responses J. Immunol., January 15, 2005; 174(2): 589 - 594. [Abstract] [Full Text] [PDF]

				M. Luo, S. M. Jones, S. M. Phare, M. J. Coffey, M. Peters-Golden, and T. G. Brock Protein Kinase A Inhibits Leukotriene Synthesis by Phosphorylation of 5-Lipoxygenase on Serine 523 J. Biol. Chem., October 1, 2004; 279(40): 41512 - 41520. [Abstract] [Full Text] [PDF]

				P. Mancuso, C. Canetti, A. Gottschalk, P. K. Tithof, and M. Peters-Golden Leptin augments alveolar macrophage leukotriene synthesis by increasing phospholipase activity and enhancing group IVC iPLA2 (cPLA2{gamma}) protein expression Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L497 - L502. [Abstract] [Full Text] [PDF]

				R. P. Charbeneau, P. J. Christensen, C. J. Chrisman, R. Paine III, G. B. Toews, M. Peters-Golden, and B. B. Moore Impaired synthesis of prostaglandin E2 by lung fibroblasts and alveolar epithelial cells from GM-CSF-/- mice: implications for fibroproliferation Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L1103 - L1111. [Abstract] [Full Text] [PDF]

				C. Bandeira-Melo, L. J. Woods, M. Phoofolo, and P. F. Weller Intracrine Cysteinyl Leukotriene Receptor-mediated Signaling of Eosinophil Vesicular Transport-mediated Interleukin-4 Secretion J. Exp. Med., September 16, 2002; 196(6): 841 - 850. [Abstract] [Full Text] [PDF]

				C. Bandeira-Melo, K. Sugiyama, L. J. Woods, M. Phoofolo, D. M. Center, W. W. Cruikshank, and P. F. Weller IL-16 Promotes Leukotriene C4 and IL-4 Release from Human Eosinophils via CD4- and Autocrine CCR3-Chemokine-Mediated Signaling J. Immunol., May 1, 2002; 168(9): 4756 - 4763. [Abstract] [Full Text] [PDF]

				D. S. Whittaker, K. S. Bahjat, L. L. Moldawer, and M. J. Clare-Salzler Autoregulation of Human Monocyte-Derived Dendritic Cell Maturation and IL-12 Production by Cyclooxygenase- 2-Mediated Prostanoid Production J. Immunol., October 15, 2000; 165(8): 4298 - 4304. [Abstract] [Full Text] [PDF]

				B. B. Moore, M. J. Coffey, P. Christensen, S. Sitterding, R. Ngan, C. A. Wilke, R. McDonald, S. M. Phare, M. Peters-Golden, R. Paine III, et al. GM-CSF Regulates Bleomycin-Induced Pulmonary Fibrosis Via a Prostaglandin-Dependent Mechanism J. Immunol., October 1, 2000; 165(7): 4032 - 4039. [Abstract] [Full Text] [PDF]

				E. LEE, T. ROBERTSON, J. SMITH, and S. KILFEATHER Leukotriene Receptor Antagonists and Synthesis Inhibitors Reverse Survival in Eosinophils of Asthmatic Individuals Am. J. Respir. Crit. Care Med., June 1, 2000; 161(6): 1881 - 1886. [Abstract] [Full Text]

				M. J. Coffey, S. M. Phare, S. Cinti, M. Peters-Golden, and P. H. Kazanjian Granulocyte-Macrophage Colony-Stimulating Factor Upregulates Reduced 5-Lipoxygenase Metabolism in Peripheral Blood Monocytes and Neutrophils in Acquired Immunodeficiency Syndrome Blood, December 1, 1999; 94(11): 3897 - 3905. [Abstract] [Full Text] [PDF]

				A. M. Healy, M. Peters-Golden, J. P. Yao, and T. G. Brock Identification of a Bipartite Nuclear Localization Sequence Necessary for Nuclear Import of 5-Lipoxygenase J. Biol. Chem., October 15, 1999; 274(42): 29812 - 29818. [Abstract] [Full Text] [PDF]

				M. Weiss, L. L. Moldawer, and E. M. Schneider Granulocyte Colony-Stimulating Factor to Prevent the Progression of Systemic Nonresponsiveness in Systemic Inflammatory Response Syndrome and Sepsis Blood, January 15, 1999; 93(2): 425 - 439. [Full Text] [PDF]

				J. F. Seymour, C. G. Begley, U. Dirksen, J. J. Presneill, N. A. Nicola, P. E. Moore, O. D. Schoch, P. vanAsperen, B. Roth, S. Burdach, et al. Attenuated Hematopoietic Response to Granulocyte-Macrophage Colony-Stimulating Factor in Patients With Acquired Pulmonary Alveolar Proteinosis Blood, October 15, 1998; 92(8): 2657 - 2667. [Abstract] [Full Text] [PDF]

				U. Martin, D. Bock, L. Arseniev, M. A. Tornetta, R. S. Ames, W. Bautsch, J. Kohl, A. Ganser, and A. Klos The Human C3a Receptor Is Expressed on Neutrophils and Monocytes, but Not on B or T Lymphocytes J. Exp. Med., July 21, 1997; 186(2): 199 - 207. [Abstract] [Full Text] [PDF]

				T. G. Brock, R. W. McNish, M. B. Bailie, and M. Peters-Golden Rapid Import of Cytosolic 5-Lipoxygenase into the Nucleus of Neutrophils after in Vivo Recruitment and in Vitro Adherence J. Biol. Chem., March 28, 1997; 272(13): 8276 - 8280. [Abstract] [Full Text] [PDF]