Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages

Authors

Nilda Rodriguez, University of IowaFollow
Kira R. Gantt, University of Iowa
Stacey Schultz-Cherry, University of Wisconsin-Madison
Selma M.B. Jeronimo, Universidade Federal do Rio Grande do NorteFollow
Eliana T. Nascimento, Universidade Federal do Rio Grande do NorteFollow
Todd L. Goldman, University of Iowa Carver College of Medicine
Thomas J. Recker, Iowa City VA Health Care SystemFollow
Melissa A. Miller, Iowa City VA Health Care System
Mary E. Wilson, University of IowaFollow

Document Type

Article

Journal/Book/Conference Title

Journal of Immunology

Volume

170

Issue

5

First Page

2613

Last Page

2620

Abstract

TGF-β is a potent regulatory cytokine that suppresses expression of inducible NO synthase and IFN-γ, and suppresses Th1 and Th2 cell development. We examined whether functionally active TGF-β is present in the local environment surrounding the invading protozoan Leishmania chagasi. Our prior data showed that TGF-β levels are significantly increased in L. chagasi-infected mice. In the current study, we found TGF-β was also abundant in bone marrows of humans with acute visceral leishmaniasis but not in those of uninfected controls. Furthermore, L. chagasi infection caused an increase in biologically active TGF-β in human macrophage cultures without changing the total TGF-β. Therefore, we investigated the means through which leishmania could augment activated but not total TGF-β. Incubation of latent TGF-β with Leishmania sp. promastigotes caused active TGF-β to be released from the latent complex. In contrast, the nonpathogenic protozoan Crithidia fasciculata could not activate TGF-β. TGF-β activation by leishmania was prevented by inhibitors of cysteine proteases and by the specific cathepsin B inhibitor CA074. Physiologic concentrations of TGF-β inhibited killing of intracellular L. chagasi in macrophages, although the phagocytosis-induced respiratory burst remained intact. In contrast, supraphysiologic concentrations of TGF-β had no effect on parasite survival. We hypothesize that the combined effect of abundant TGF-β stores at extracellular sites during infection, and the ability of the parasite to activate TGF-β in its local environment, leads to high levels of active TGF-β in the vicinity of the infected macrophage. Locally activated TGF-β could, in turn, enhance parasite survival through its effects on innate and adaptive immune responses.

Department

Department of Biology

Original Publication Date

3-1-2003

DOI of published version

10.4049/jimmunol.170.5.2613

Recommended Citation

Rodriguez, Nilda; Gantt, Kira R.; Schultz-Cherry, Stacey; Jeronimo, Selma M.B.; Nascimento, Eliana T.; Goldman, Todd L.; Recker, Thomas J.; Miller, Melissa A.; and Wilson, Mary E., "Activation of TGF-β by Leishmania chagasi: Importance for Parasite Survival in Macrophages" (2003). Faculty Publications. 6355.
https://scholarworks.uni.edu/facpub/6355