CHEMOKINES INDUCED BY INFECTION OF MONONUCLEAR PHAGOCYTES WITH MYCOBACTERIA AND PRESENT IN LUNG ALVEOLI DURING ACTIVE PULMONARY TUBERCULOSIS

The capacity of Mycobacterium tuberculosis (MTB) to induce production of chemokines with known chemotactic activity for monocytes and lympho cytes, the cellular building blocks of granulomas, was investigated. T hese chemokines included regulated upon activation, normal T cell expr essed and secreted (RANTES), monocyte chemotactic protein-1 (MCP-1), a nd macrophage inflammatory protein-1 alpha (MIP-1 alpha). MTB stimulat ed production of MCP-1 and MIP-1 alpha by blood monocytes (MN) and alv eolar macrophages (AM). MTB infection of MN and AM stimulated release but not production of RANTES. AM produced or released significantly hi gher levels than MN of RANTES (by 2.1-fold), MCP-1 (by 6.9-fold), and MIP-1 alpha (by 5.5-fold) (P < 0.05 for each). This study also confirm ed that MTB-infected AM produce the chemokine interleukin (IL)-8. MTB infection of AM resulted in increased steady-state expression of messe nger RNA (mRNA) for MCP-1 and MIP-1 alpha and minimal increased expres sion of RANTES mRNA. Both an avirulent (H37Ra) and a virulent (H37Rv) strain of MTB and purified protein derivative of H37Rv but not latex b eads induced production of chemokines. Supernatants of MTB-infected ce lls demonstrated chemotactic activity for both monocytes and lymphocyt es partially inhibitable by neutralizing antibodies against the chemok ines studied. Bronchoalveolar lavage fluid from patients with active p ulmonary tuberculosis as compared with healthy control subjects contai ned increased levels of RANTES (by 8-fold), MCP-1 (by 2.7-fold), and I L-8 (by 8.9-fold) (P < 0.05), but not MIP-1 alpha, as compared with he althy control subjects. Thus, multiple chemokines may be involved in r ecruitment of cells for granuloma formation in tuberculosis.