Bioactivation of latent transforming growth factor β1 by Mycobacterium tuberculosis in human mononuclear phagocytes

Abstract

Biologically active transforming growth factor beta 1 (TGFβ1) has been identified at sites of Mycobacterium tuberculosis (MTB) infection in the lung; however, the underlying mechanism(s) for its activation is not clear. Here using an enzyme-linked immunospot assay for TGFβ1, we show that human blood monocytes (MN) and alveolar macrophages (AM) produce bioactive TGFβ1 upon stimulation by MTB. However, only MTB-stimulated MN increased TGFβ1 production on a per cell basis. The frequency of TGFβ1-producing MN was reduced by an inhibitor of plasmin, bdellin, indicating a role for plasmin pathways in the bioactivation of cytokine. The expression of urokinase plasminogen activator receptor (uPAR) mRNA and both surface and soluble uPAR (CD87) was increased in MTB-activated MN. However, antibody neutralization of uPAR suppressed bioactive TGFβ1 in MN alone. Thus, the more immature MN, which are continuously recruited to the lung during tuberculosis (TB), have a higher capacity to bioactivate TGFβ1 by expression of components of the plasmin pathway. Excess production and bioactivation of TGFβ1 at sites of MTB infection may undermine host immune responses during TB. © 2005 Blackwell Publishing Ltd.