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Infection and Immunity, November 1999, p. 5730-5735, Vol. 67, No. 11
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Interaction of Mycobacterium
tuberculosis-Induced Transforming Growth Factor
1 and
Interleukin-10
Catherine
Othieno,1
Christina S.
Hirsch,2
Beverly D.
Hamilton,2
Katalin
Wilkinson,2
Jerrold J.
Ellner,2 and
Zahra
Toossi2,3,*
Department of Medicine, Case Western Reserve
University and University Hospitals of
Cleveland,2 and Veterans Affairs Medical
Center,3 Cleveland, Ohio 44106, and
Makerere University, Kampala, Uganda1
Received 19 March 1999/Returned for modification 5 May
1999/Accepted 5 August 1999
Mycobacterium tuberculosis is associated with the
activation of cytokine circuits both at sites of active tuberculosis in vivo and in cultures of mononuclear cells stimulated by M. tuberculosis or its components in vitro. Interactive stimulatory
and/or inhibitory pathways are established between cytokines, which may
result in potentiation or attenuation of the effects of each molecule
on T-cell responses. Here we examined the interaction of transforming growth factor
1 (TGF-
1) and interleukin-10 (IL-10) in purified protein derivative (PPD)-stimulated human mononuclear cell cultures in
vitro. TGF-
1 induced monocyte IL-10 (but not tumor necrosis factor
alpha) production (by 70-fold, P < 0.02) and mRNA
expression in the absence but not in the presence of PPD. Both
exogenous recombinant (r) IL-10 and rTGF-
1 independently suppressed
the production of PPD-induced gamma interferon (IFN-
) in mononuclear cells from PPD skin test-positive individuals. Synergistic suppression of IFN-
in cultures containing both rTGF-
1 and rIL-10 was only seen when the responder cell population were peripheral blood mononuclear cells (PBMC) and not monocyte-depleted mononuclear cells
and when PBMC were pretreated with rTGF-
1 but not with rIL-10.
Suppression of PPD-induced IFN-
in PBMC containing both rTGF-
1 (1 ng/ml) and rIL-10 (100 pg/ml) was 1.5-fold higher (P < 0.05) than cultures containing TGF-
1 alone and 5.7-fold higher (P < 0.004) than cultures containing IL-10 alone.
Also, neutralization of endogenous TGF-
1 and IL-10 together enhanced
PPD-induced IFN-
in PBMC in a synergistic manner. Thus, TGF-
1 and
IL-10 together potentiate the downmodulatory effect on M. tuberculosis-induced T-cell production of IFN-
, and TGF-
1
alone enhances IL-10 production. At sites of active M. tuberculosis infection, these interactions may be conducive to
the suppression of mononuclear cell functions.
*
Corresponding author. Mailing address: Division of
Infectious Diseases, Case Western Reserve University, Biomedical
Research Bldg., 10900 Euclid Ave., Cleveland, OH 44106-4984. Phone:
(216) 368-4843. Fax: (216) 368-2034. E-mail:
zxt2{at}po.cwru.edu.
Infection and Immunity, November 1999, p. 5730-5735, Vol. 67, No. 11
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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