The Journal of Immunology, Vol 146, Issue 6 1849-1857, Copyright © 1991 by American Association of Immunologists

ARTICLES

Differential susceptibility of activated macrophage cytotoxic effector reactions to the suppressive effects of transforming growth factor-beta 1

BJ Nelson, P Ralph, SJ Green and CA Nacy
Department of Cellular Immunology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.

We examined the effects of TGF-beta 1 on induction of several activated macrophage antimicrobial activities against the protozoan parasite Leishmania, and on induction of tumoricidal activity against the fibrosarcoma tumor target 1023. TGF-beta by itself did not affect the viability of either the intracellular or extracellular target in concentrations up to 200 ng/ml. As little as 1 ng/ml TGF-beta, however, suppressed more than 70% of the intracellular killing activity of macrophages treated with lymphokines. In contrast, more than 100 ng/ml TGF-beta was required to suppress intracellular killing by cells activated with an equivalent amount of recombinant IFN-gamma. Addition of TGF-beta for up to 30 min after exposure to activation factors significantly reduced macrophage killing of intracellular parasites. Pretreatment of macrophages with TGF-beta was even more effective: treatment of cells with TGF-beta for 4 h before addition of activation factors abolished all macrophage intracellular killing activity. Regardless of treatment sequence, however, TGF-beta had absolutely no effect, at any concentration tested, on activated macrophage resistance to infection induced by lymphokines or by the cooperative interaction of IFN-gamma and IL-4. Effects of TGF-beta on tumoricidal activity of activated macrophages was intermediate to that of its effects on intracellular killing or resistance to infection. Lymphokine-induced tumor cytotoxicity was marginally (25%) affected by TGF-beta; 200 ng/ml was able to suppress IFN-gamma-induced tumoricidal activity by 40%. Thus, TGF-beta dramatically suppressed certain activated macrophage cytotoxic effector reactions, but was only partially or not at all effective against others, even when the same activation agent (IFN- gamma) was used. The biochemical target for TGF-beta suppressive activity in these reactions may be the pathway for nitric oxide production from L-arginine, because TGF-beta also inhibited the generation of nitric oxide by cytokine-activated macrophages.

This article has been cited by other articles:

				C. M. Bosio, H. Bielefeldt-Ohmann, and J. T. Belisle Active Suppression of the Pulmonary Immune Response by Francisella tularensis Schu4 J. Immunol., April 1, 2007; 178(7): 4538 - 4547. [Abstract] [Full Text] [PDF]

				H. Takaki, Y. Minoda, K. Koga, G. Takaesu, A. Yoshimura, and T. Kobayashi TGF-beta1 suppresses IFN-gamma-induced NO production in macrophages by suppressing STAT1 activation and accelerating iNOS protein degradation. Genes Cells, August 1, 2006; 11(8): 871 - 882. [Abstract] [Full Text] [PDF]

				J. L. M. Wanderley, M. E. C. Moreira, A. Benjamin, A. C. Bonomo, and M. A. Barcinski Mimicry of Apoptotic Cells by Exposing Phosphatidylserine Participates in the Establishment of Amastigotes of Leishmania (L) amazonensis in Mammalian Hosts J. Immunol., February 1, 2006; 176(3): 1834 - 1839. [Abstract] [Full Text] [PDF]

				M. Murano, X. Xiong, N. Murano, J. L. Salzer, J. J. Lafaille, and V. K. Tsiagbe Latent TGF-{beta}1-transduced CD4+ T cells suppress the progression of allergic encephalomyelitis J. Leukoc. Biol., January 1, 2006; 79(1): 140 - 146. [Abstract] [Full Text] [PDF]

				M. Eriksson, S. K. Meadows, C. R. Wira, and C. L. Sentman Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-{beta} J. Leukoc. Biol., September 1, 2004; 76(3): 667 - 675. [Abstract] [Full Text] [PDF]

				L. Gorelik, S. Constant, and R. A. Flavell Mechanism of Transforming Growth Factor {beta}-induced Inhibition of T Helper Type 1 Differentiation J. Exp. Med., June 3, 2002; 195(11): 1499 - 1505. [Abstract] [Full Text] [PDF]

				P. C. Melby, B. Chandrasekar, W. Zhao, and J. E. Coe The Hamster as a Model of Human Visceral Leishmaniasis: Progressive Disease and Impaired Generation of Nitric Oxide in the Face of a Prominent Th1-Like Cytokine Response J. Immunol., February 1, 2001; 166(3): 1912 - 1920. [Abstract] [Full Text] [PDF]

				L. H. Kasper and D. Buzoni-Gatel Ups and Downs of Mucosal Cellular Immunity against Protozoan Parasites Infect. Immun., January 1, 2001; 69(1): 1 - 8. [Full Text] [PDF]

				K. M. Drescher, P. D. Murray, X. Lin, J. A. Carlino, and M. Rodriguez TGF-{beta}2 Reduces Demyelination, Virus Antigen Expression, and Macrophage Recruitment in a Viral Model of Multiple Sclerosis J. Immunol., March 15, 2000; 164(6): 3207 - 3213. [Abstract] [Full Text] [PDF]

				A. Coste, J.-P. Lefaucheur, Q.-P. Wang, E. Lesprit, F. Poron, R. Peynegre, and E. Escudier Expression of the Transforming Growth Factor {beta} Isoforms in Inflammatory Cells of Nasal Polyps Arch Otolaryngol Head Neck Surg, December 1, 1998; 124(12): 1361 - 1366. [Abstract] [Full Text] [PDF]

				L. Z. Chen, G. M. Hochwald, C. Huang, G. Dakin, H. Tao, C. Cheng, W. J. Simmons, G. Dranoff, and G. J. Thorbecke Gene therapy in allergic encephalomyelitis using myelin basic protein-specific T cells engineered to express latent transforming growth factor-beta 1 PNAS, October 13, 1998; 95(21): 12516 - 12521. [Abstract] [Full Text] [PDF]

				E. Bohn, E. Schmitt, C. Bielfeldt, A. Noll, R. Schulte, and I. B. Autenrieth Ambiguous Role of Interleukin-12 in Yersinia enterocolitica Infection in Susceptible and Resistant Mouse Strains Infect. Immun., May 1, 1998; 66(5): 2213 - 2220. [Abstract] [Full Text] [PDF]

				M. Takeuchi, P. Alard, and J. W. Streilein TGF-{beta} Promotes Immune Deviation by Altering Accessory Signals of Antigen-Presenting Cells J. Immunol., February 15, 1998; 160(4): 1589 - 1597. [Abstract] [Full Text] [PDF]

				M Barral-Netto, A Barral, C. Brownell, Y. Skeiky, L. Ellingsworth, D. Twardzik, and S. Reed Transforming growth factor-beta in leishmanial infection: a parasite escape mechanism Science, July 24, 1992; 257(5069): 545 - 548. [Abstract] [PDF]