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Matrix Metalloproteinase-1 Is Regulated in Tuberculosis by a p38 MAPK-Dependent, p-Aminosalicylic Acid-Sensitive Signaling Cascade¹

Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Campus, London, United Kingdom

Mycobacterium tuberculosis (M. tb) must cause lung disease to spread. Matrix metalloproteinases (MMPs) degrade the extracellular matrix and are implicated in tuberculosis-driven tissue destruction. We investigated signaling pathways regulating macrophage MMP-1 and -7 in human pulmonary tuberculosis and examine the hypothesis that the antimycobacterial drug p-aminosalicylic acid acts by inhibiting such pathways. In primary human macrophages, M. tb up-regulates gene expression and secretion of MMP-1 (interstitial collagenase) and MMP-7 (matrilysin). In tuberculosis patients, immunohistochemical analysis of lung biopsies demonstrates that p38 MAPK is phosphorylated in macrophages surrounding granulomas. In vitro, M. tb drives p38 phosphorylation. p38 inhibition suppresses M. tb-dependent MMP-1 secretion by 57.8% and concurrently increases secretion of its specific inhibitor TIMP-1 by 243.7%, demonstrating that p38 activity regulates matrix degradation by macrophages. p38 signals downstream to the cyclooxygenase 2/PGE₂ pathway. p-Aminosalicyclic acid, an agent used to treat drug-resistant tuberculosis, inhibits M. tb-driven MMP-1 but not MMP-7 gene expression and secretion. PAS acts by blocking PGE₂ production without affecting M. tb growth. In summary, p-aminosalicyclic acid decreases MMP-1 activity by inhibiting a p38 MAPK-PG signaling cascade, suggesting that this pathway is a therapeutic target to reduce inflammatory tissue destruction in tuberculosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institute for Health Research, the Medical Research Council (U.K.), and the Hammersmith Hospitals Trustees Research Committee. J.S.F. and P.E. are grateful for support from the National Institute for Health Research Biomedical Research Centre funding scheme at Imperial College.

² L.R. and J.A.G. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Paul T. Elkington, Department of Infectious Diseases and Immunity, Imperial College London, Hammersmith Campus, Du Cane Road, London W12 0NN, U.K. E-mail address: p.elkington{at}imperial.ac.uk

⁴ Abbreviations used in this paper used: M. tb, Mycobacterium tuberculosis; MMP, matrix metalloproteinase; PAS, p-aminosalicylic acid; TIMP, tissue inhibitor of metalloproteinase; COX, cyclooxygenase; MOI, multiplicity of infection.