Mycobacterial Evasion of Immunity Via Cytokine Dysregulation: A Potential Role for Mitogen-Activated Protein Kinase Phosphatase-1

Abstract

Introduction: Mycobacterium tuberculosis (MTB) is a major cause of morbidity and mortality in the world. To combat against this pathogen, immune cells release cytokines including tumour necrosis factor (TNF)-α, which plays a pivotal role in the development of protective granulomas consisting of macrophages and other immune cells to contain the mycobacteria. Our previous results showed that Bacillus Calmette Guerin (BCG), a mycobacterial model used to investigate the immune response against MTB, stimulates the induction of TNF-α via a double-stranded RNA-dependent protein kinase (PKR) and mitogen-activated protein kinase (MAPK) in human blood monocytes. Since MAPK is regulated by MAPK phosphatase-1 (MKP-1) in response to lipopolysaccharide (LPS), the involvement of MKP-1 in BCG-induced MAPK activation and its consequent cytokine expression was examined. Methods: Primary human blood monocytes were treated with BCG and assayed for MKP-1 expression by quantitative RT-PCR and Western analysis. Results: Our results demonstrated that following exposure to BCG, there was an increase in the expression of MKP-1. Additionally, there was a significant abrogation of BCG-induced MKP-1 expression in the presence of the p38 MAPK and ERK1/2 inhibitors. The results suggested that the induction of MKP-1 was regulated by p38 MAPK and ERK1/2 in response to BCG activation. Next, the roles of MKP-1 in BCG-induced MAPK activation and TNF-α expression were elucidated with the use of MKP-1 siRNA for gene-specific knock-down. Surprisingly, when MKP-1 was blocked by MKP-1 siRNA, there was a significant decrease in the levels of phospho-MAPK and TNF-α inducible by BCG, indicating the phosphatase plays a pivotal role in cellular defense against mycobacterial infection. Conclusion: Taken together, MKP-1 plays a critical role in the regulation of TNF induction in response to mycobacterial infection, and its induction may suggest an effective host defense mechanism to combat the pathogen invasion. Conflict of Interest Statements: There is no conflict of interest (supported in part by grants to ASL from RFCID and RGC-CERG).