Restoration of impaired free radical generation and proinflammatory cytokines by MCP-1 in mycobacterial pathogenesis

Abstract

Mycobacterium tuberculosis exerts its pathogenic effects mainly via its cell wall glycolipid called Mannosylated Lipoarabinomannan (Man-LAM), which subverts the cellular inflammatory responses by the suppression of superoxide anion generation in earlier hours, and nitric oxide (NO) generation at later hours of pathogenic invasion. In this paper, we have shown the prophylactic effect of C-C chemokines, both in vitro and in vivo. Exogenous administration of C-C chemokines, particularly monocyte chemoattractant protein (MCP)-1, led to the induction of superoxide anion generation via the restoration of impaired protein kinase C (PKC) signalling in Man-LAM-treated macrophages. Monocyte chemoattractant protein-1 could also potently induce NO generation by upregulation of the proinflammatory cytokines tumour necrosis factor-alpha and interleukin-12 from Man-LAM-treated macrophages accompanied by inhibition of anti-inflammatory responses. Our in vivo observations clearly exhibited effective restoration of impaired PKC signalling as well as proinflammatory cytokine expression by MCP-1 in Man-LAM treated as well as M. tuberculosis H37Rv-infected C57BL/6 mice. We also observed, as direct evidence, that MCP-1 induced a significant reduction of the number of viable tubercle bacilli in the lungs and spleen of infected mice. Collectively, our findings strongly suggest the effectiveness of MCP-1 as a potent immunoprophylactic tool for controlling the mycobacterial establishment within the host.