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‐α 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.

Mannosylated Lipoarabinomannans from Mycobacterium Avium Subsp. Paratuberculosis Alters the Inflammatory Response by Bovine Macrophages and Suppresses Killing of Mycobacterium Avium Subsp. Avium Organisms

“…Likewise, Man-LAM from Mtb has been shown to suppress oxygen radical and nitric oxide generation. [21]. Other major effects attributed to Man-LAM derived from Mtb include inhibition of macrophage apoptosis and inhibition of phagosome-lysosome fusion [19], [22].…”

Association of Reduced Tumor Necrosis Factor Alpha, Gamma Interferon, and Interleukin-1β (IL-1β) but Increased IL-10 Expression with Improved Chest Radiography in Patients with Pulmonary Tuberculosis

“…The C-C chemokines (two adjacent cysteine residues proximal to the amino terminus, such as MCP-1 and macrophage-inhibitory protein-1␣) and the C-X-C chemokines (such as IL-8, IP-10, and IL-1␤) are putatively involved in the orchestrated recruitment of inflammatory cells conducive to granuloma formation (1,5). MCP-1 expression has correlated with potent nitric oxide generation and the subsequent reduction in the M. tuberculosis loads in murine lungs (19). Similarly, our data provide a correlation between normalized MCP-1 levels and the resolution of the M. tuberculosis infection in patients, as de- In contrast, the interpatient variability of the IP-10 plasma levels in our study suggested that the intrapatient determination of IP-10 expression kinetics may provide a stronger correlation to the anti-M. tuberculosis therapeutic response than the threshold IP-10 level.…”

Expression and regulation of chemokines in mycobacterial infection

“…46 Importantly, it has been demonstrated that exogenous administration of MCP-1, led to the induction of superoxide anion generation via the restoration of impaired protein kinase C signaling in Man-LAM-treated macrophages, indicating the effectiveness of MCP-1 as a potent immunoprophylactic tool for controlling the mycobacterial establishment within the host. 47 In addition, it has been demonstrated that M. tuberculosisinduced chemokine secretion from macrophages is regulated by different mycobacterial cell wall components. 48 The CC-chemokine subfamily members, particularly CCL5, are potent leukocyte activators and chemoattractants, which have an important role in granuloma formation.…”