A combination of a transforming growth factor-β antagonist and an inhibitor of cyclooxygenase is an effective treatment for murine pulmonary tuberculosis

Abstract

SummaryTransforming growth factor-beta (TGF-β β β β ) and prostaglandins (PG) regulate the cell-mediated immune response, so it has been proposed that they affect the progression of pulmonary tuberculosis. Here we report that the administration of soluble betaglycan, a potent TGF-β β β β antagonist, and niflumic acid, a PG synthesis inhibitor, during the chronic phase of experimental murine tuberculosis enhanced Th1 and decreased Th2 cytokines, increased the expression of iNOS and reduced pulmonary inflammation, fibrosis and bacillary load. This immunotherapeutic approach resulted in significant control of the disease comparable to that achieved by anti-microbial treatment alone. Importantly, the combination of immunotherapy and anti-microbials resulted in an accelerated clearance of bacilli from the lung. These results confirm that TGF-β β β β and PG have a central pathophysiological role in the progression of pulmonary tuberculosis in the mouse and suggest that the addition of immunotherapy to conventional anti-microbial drugs might result in improved treatment of the disease.

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

“…Up-regulation of MMP-9 expression in murine macrophages by Mycobacterium avium is PGE 2 dependent (39). During the chronic phase of experimental murine tuberculosis, administration of a PG synthesis inhibitor with a TGF-␤ antagonist reduced pulmonary inflammation, fibrosis, and bacillary load (40), consistent with our hypothesis that excess COX-2 activity is associated with immunopathology. Similarly, inhibition of PG accumulation with either aspirin or ibuprofen increased the efficacy of pyrazinamide in a murine model (41).…”

Active Suppression of the Pulmonary Immune Response by Francisella tularensis Schu4

“…For example, the inhibition of lung NK cells by alveolar macrophages is through the production of both TGF-␤ and PGE 2 by the macrophages (35). The neutralization of TGF-␤ and the simultaneous inhibition of prostaglandins significantly increased the production of TNF-␣ and NO while inhibiting replication of M. tuberculosis in the lung (36). More recently Woolard et al demonstrated that the elicitation of PGE 2 by LVS contributes to the successful replication of the bacterium in macrophages while suppressing T cell responses in the lung (37).…”

Orally Administered Mycobacterium vaccae Modulates Expression of Immunoregulatory Molecules in BALB/c Mice with Pulmonary Tuberculosis

“…This might explain why a neutralizing antibody to IL-4 is therapeutic in another highdose challenge mouse model of TB (26) and suggests that reducing IL-4 is likely to be therapeutically useful. Similarly inhibition of TGF-␤ by administering soluble type III TGF-␤ receptors is also therapeutic in this model (12).…”