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.
Subject(s)
Chemokine CCL2/pharmacology , Mycobacterium tuberculosis , Tuberculosis/immunology , Tuberculosis/microbiology , Animals , Antigens, Bacterial/pharmacology , Chemokine CCL2/genetics , Chemokine CCL3/genetics , Colony Count, Microbial , Interleukin-12/metabolism , Lipopolysaccharides/pharmacology , Lung/microbiology , Macrophages, Peritoneal/drug effects , Macrophages, Peritoneal/immunology , Macrophages, Peritoneal/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mycobacterium tuberculosis/isolation & purification , Mycobacterium tuberculosis/pathogenicity , Nitric Oxide/metabolism , Protein Kinases/metabolism , Recombinant Proteins/pharmacology , Signal Transduction/drug effects , Spleen/microbiology , Superoxides/metabolism , Tumor Necrosis Factor-alpha/metabolism , VirulenceABSTRACT
The resolution from leishmanial infection is dependent on the coordinated interactions between the components of the cell mediated immune system and the activation of T-cell population into appropriate cytokine production and the activation of macrophages. Earlier reports established that C-C chemokines particularly macrophage inflammatory protein (MIP)-1alpha and macrophage chemoattractant protein (MCP)-1 restrict the parasitic burden via the regulation of impaired protein kinase C (PKC) signalling and induction of free-radical generation in murine leishmaniasis. This study explored the role of MIP-1alpha and MCP-1 in the induction of T helper 1 (Th1) immune response and suppression of T helper 2 (Th2) response in Leishmania donovani-infected BALB/c mice. These chemokines induced the known pro-inflammatory cytokine interleukin (IL)-12 secretion and inhibited the secretion of anti-inflammatory cytokines IL-10 and transforming growth factor-beta in infected macrophages. Impaired antigen presentation capability of infected macrophages was also restored by the chemokine treatment. C-C chemokine treatment resulted in reduced levels of mRNA expression of IL-10, but increased levels of mRNA expression of IL-12p40, interferon (IFN)-gamma, tumour necrosis factor-alpha and inducible nitric oxide synthase in both liver mononuclear cells as well as in splenocytes, reflecting a switch of CD4+ differentiation from Th2 to Th1. Flow cytometric analysis of infected spleen cells suggested that C-C chemokine treatment enhances the CD4+ T cells to produce increased levels of IFN-gamma. These studies hypothesize a promising immuno-prophylactic effect of chemokines against leishmaniasis by induction of Th1 cytokine release imparting a long-term resistance.
