Bioactivation of latent transforming growth factor beta1 by Mycobacterium tuberculosis in human mononuclear phagocytes.
Biologically active transforming growth factor beta 1 (TGFbeta1) 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 TGFbeta1, we show that human blood monocytes (MN) and alveolar macrophages (AM) produce bioactive TGFbeta1 upon stimulation by MTB. However, only MTB-stimulated MN increased TGFbeta1 production on a per cell basis. The frequency of TGFbeta1-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 TGFbeta1 in MN alone. Thus, the more immature MN, which are continuously recruited to the lung during tuberculosis (TB), have a higher capacity to bioactivate TGFbeta1 by expression of components of the plasmin pathway. Excess production and bioactivation of TGFbeta1 at sites of MTB infection may undermine host immune responses during TB.
Aung
H
H
Division of Infectious Disease, Department of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA.
Wu
M
M
Johnson
J L
JL
Hirsch
C S
CS
Toossi
Z
Z
D000328:Adult; D002478:Cells, Cultured; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D011480:Protease Inhibitors / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
C524898:PLAUR protein, human; D011480:Protease Inhibitors; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D005341:Fibrinolysin