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Infection and Immunity, May 2000, p. 2827-2836, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

In Situ Production of Gamma Interferon, Interleukin-4, and Tumor Necrosis Factor Alpha mRNA in Human Lung Tuberculous Granulomas

Gael Fenhalls,1,2 Anthony Wong,3 Juanita Bezuidenhout,1,4 Paul van Helden,1,2 Philip Bardin,1,5 and Pauline T. Lukey3,*

MRC Center for Molecular and Cellular Biology1 and Departments of Medical Biochemistry,2 Anatomical Pathology,4 and Internal Medicine,5 University of Stellenbosch Medical School, Cape Town, South Africa, and Glaxo Wellcome Research and Development, Medicines Research Center, Stevenage, United Kingdom3

Received 14 June 1999/Returned for modification 25 August 1999/Accepted 10 October 1999

Human tuberculous granulomas from five adults undergoing surgery for hemoptysis were analyzed by nonradioactive in situ hybridization for tumor necrosis factor alpha (TNF-alpha ), gamma interferon (IFN-gamma ), and interleukin-4 (IL-4) gene expression. All of the patients produced TNF-alpha mRNA. Three patients stained positive for both IFN-gamma and IL-4 mRNA; the other two stained positive for IFN-gamma but not IL-4 mRNA. Heterogeneity between the granulomas was observed in those patients staining positive for both IFN-gamma and IL-4 mRNA; these patients exhibited granulomas having IFN-gamma and not IL-4 mRNA as well as granulomas positive for both cytokine mRNAs. There was no evidence of caseation in these granulomas, and the cytokine patterns may represent events in the evolution of the granuloma. However, in those granulomas exhibiting caseous necrosis, very little IFN-gamma or IL-4 mRNA was observed, implying that progression of the granuloma is accompanied by a down regulation of T-cell responses. TNF-alpha mRNA expression was highest in patients with both IFN-gamma and IL-4 mRNA. Populations of CD68 positive macrophage-like cells within the granulomas produce mRNA for TNF-alpha , IFN-gamma , and IL-4. This implies that macrophages within the tuberculous granuloma may not be dependent on T-cell cytokines for modulation of their function but may be able to regulate their own activation state and that of the surrounding T cells. These findings have implications on the delivery of immunotherapies to patients with tuberculosis.

* Corresponding author. Mailing address: Glaxo Wellcome Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom. Phone: 99 1438 76 4968. Fax: 99 1438 76 4898. E-mail: PTL46978{at}GLAXOWELLCOME.CO.UK.

Infection and Immunity, May 2000, p. 2827-2836, Vol. 68, No. 5
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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