Virulence of Mycobacterium tuberculosis affects interleukin-8, monocyte chemoattractant protein-1 and interleukin-10 production by human mononuclear phagocytes

Microbial virulence and cytokine-mediated immune responses to Mycobacterium tuberculosis infection are important determinants of the pathogenesis of h uman tuberculosis. To determine the interrelationship between mycobacterial virulence and cytokine induction, human monocytes and monocyte-derived mac rophages were infected with attenuated (H37Ra) and virulent (H37Rv and CH30 6) strains of M. tuberculosis and the amount of proinflammatory [interleuki n (IL-8 and monocyte chemoattractant protein (MCP)- 1] and inhibitory (IL-1 0) cytokines was measured in the culture supernatants by enzyme-linked immu nosorbent assay (ELISA). Infection with live bacilli induced de novo synthe sis of IL-8, MCP-1 and IL-10, since cytokine release was abolished when cel ls were preincubated with the protein synthesis inhibitor cycloheximide. A differential production of antiinflammatory and inhibitory cytokines was ob served. The amount of IL-8 and MCP-1 release was inversely related to strai n virulence, the attenuated H37Ra strain being more prone than virulent str ains to induce secretion of chemokines. In contrast, virulent strains induc ed greater amounts of the inhibitory cytokine IL-10. Efficient upregulation of IL-10 synthesis, but not of chemokines, required infection of cells wit h live bacilli, since heat killing of organisms or challenge with soluble m ycobacterial products completely abrogated the effect. Moreover, cells infe cted with virulent strains produced IL-10 even at a very low bacillus-to-ce ll ratio and secreted IL-10 continuously during the 96 h that followed infe ction. The results Suggest that the degree of virulence affects host cell r esponses to M. tuberculosis infection. Continued production of IL-10 may be one of the means by which M. tuberculosis downregulates acute local inflam matory reactions, favoring the development of tuberculosis.