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Infection and Immunity, September 2001, p. 5661-5670, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5661-5670.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Production of Matrix Metalloproteinases in Response to Mycobacterial Infection

Marianne Quiding-Järbrink,* Debbie A. Smith, and Gregory J. Bancroft

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London WC1E 7HT, United Kingdom

Received 17 August 2000/Returned for modification 22 November 2000/Accepted 29 May 2001

Matrix metalloproteinases (MMPs) constitute a large family of enzymes with specificity for the various proteins of the extracellular matrix which are implicated in tissue remodeling processes and chronic inflammatory conditions. To investigate the role of MMPs in immunity to mycobacterial infections, we incubated murine peritoneal macrophages with viable Mycobacterium bovis BCG or Mycobacterium tuberculosis H37Rv and assayed MMP activity in the supernatants by zymography. Resting macrophages secreted only small amounts of MMP-9 (gelatinase B), but secretion increased dramatically in a dose-dependent manner in response to either BCG or M. tuberculosis in vitro. Incubation with mycobacteria also induced increased MMP-2 (gelatinase A) activity. Neutralization of tumor necrosis alpha (TNF-alpha ), and to a lesser extent interleukin 18 (IL-18), substantially reduced MMP production in response to mycobacteria. Exogenous addition of TNF-alpha or IL-18 induced macrophages to express MMPs, even in the absence of bacteria. The immunoregulatory cytokines gamma interferon (IFN-gamma ), IL-4, and IL-10 all suppressed BCG-induced MMP production, but through different mechanisms. IFN-gamma treatment increased macrophage secretion of TNF-alpha but still reduced their MMP activity. Conversely, IL-4 and IL-10 seemed to act by reducing the amount of TNF-alpha available to the macrophages. Finally, infection of BALB/c or severe combined immunodeficiency (SCID) mice with either BCG or M. tuberculosis induced substantial increases in MMP-9 activity in infected tissues. In conclusion, we show that mycobacterial infection induces MMP-9 activity both in vitro and in vivo and that this is regulated by TNF-alpha , IL-18, and IFN-gamma . These findings indicate a possible contribution of MMPs to tissue remodeling processes that occur in mycobacterial infections.

* Corresponding author. Present address: Dept. of Medical Microbiology & Immunology, Box 435, Göteborg University, SE-405 30 Göteborg, Sweden. Phone: 46-31-342 4492. Fax: 46-31-826976. E-mail: marianne.quiding{at}microbio.gu.se.

Infection and Immunity, September 2001, p. 5661-5670, Vol. 69, No. 9
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.9.5661-5670.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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