UP-REGULATION OF ALVEOLAR MACROPHAGE PLATELET-DERIVED GROWTH FACTOR-B(PDGF-B) MESSENGER-RNA BY INTERFERON-GAMMA FROM MYCOBACTERIUM-TUBERCULOSIS ANTIGEN (PPD)-STIMULATED LYMPHOCYTES

Macrophage production of PDGF-B is believed to be important in the pat hogenesis of diseases where chronic lung inflammation develops into fi brosis. Since tuberculosis is characterized by chronic inflammation an d tissue fibrosis, we asked if lymphokines from lymphocytes stimulated by the Mycobacterium tuberculosis antigen PPD, contained factors capa ble of increasing human alveolar macrophage PDGF-B mRNA. Supernatants from both phytohaemagglutinin (PHA)- and purified protein derivative ( PPD)-stimulated lymphocytes, when added to macrophages, induced an inc rease in the mRNA of PDGF-B, but not transforming growth factor-beta ( TGF-beta). When lymphocytes from contacts of patients with tuberculosi s, patients with tuberculosis, and normal subjects were compared follo wing PPD stimulation, the lymphocytes from the contacts had the greate st proliferation response, the greatest production of interferon-gamma (IFN-gamma), and their lymphokines induced the greatest increase in P DGF-B mRNA in macrophages. Recombinant human IFN-gamma reproduced this ability of lymphokines to increase macrophage PDGF-B mRNA. Finally, t he increase in macrophage PDGF-B mRNA following incubation with supern atants from PPD-stimulated lymphocytes was shown to be due to IFN-gamm a, when the increase in macrophage PDGF-B mRNA was prevented by additi on of anti-human IFN-gamma antibody to the lymphocyte supernatant. Thi s study indicated that antigen-stimulated lymphocytes released IFN-gam ma, which in tum resulted in an increase in PDGF-B mRNA in alveolar ma crophages. Such a mechanism provides a link between the DTH response a nd the first stages of a fibrotic reaction, and may offer an explanati on for the progression of chronic inflammation to fibrosis, as occurs in the lungs of patients with untreated pulmonary tuberculosis.