A novel anti-mycobacterial function of mitogen-activated protein kinase phosphatase-1.
BACKGROUND
Mycobacterium tuberculosis (MTB) is a major cause of morbidity and mortality in the world. To combat against this pathogen, immune cells release cytokines including tumor necrosis factor-alpha (TNF-alpha), which is pivotal in the development of protective granulomas. Our previous results showed that Bacillus Calmette Guerin (BCG), a mycobacterium used as a model to investigate the immune response against MTB, stimulates the induction of TNF-alpha via mitogen-activated protein kinase (MAPK) in human blood monocytes. Since MAPK phosphatase-1 (MKP-1) is known to regulate MAPK activities, we examined whether MKP-1 plays a role in BCG-induced MAPK activation and cytokine expression.


RESULTS
Primary human blood monocytes were treated with BCG and assayed for MKP-1 expression. Our results demonstrated that following exposure to BCG, there was an increase in the expression of MKP-1. Additionally, the induction of MKP-1 was regulated by p38 MAPK and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Surprisingly, when MKP-1 expression was blocked by its specific siRNA, there was a significant decrease in the levels of phospho-MAPK (p38 MAPK and ERK1/2) and TNF-alpha inducible by BCG.


CONCLUSIONS
Since TNF-alpha is pivotal in granuloma formation, the results indicated an unexpected positive function of MKP-1 against mycobacterial infection as opposed to its usual phosphatase activity.
Cheung
Benny K W
BK
Cytokine Biology Group, Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China. bennykwc@graduate.hku.hk
Yim
Howard C H
HC
Lee
Norris C M
NC
Lau
Allan S Y
AS
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000502:physiology*; D004790:Enzyme Induction; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008074:Lipoproteins / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology; D009000:Monocytes / Q000502:physiology; D009163:Mycobacterium bovis / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
D000900:Anti-Bacterial Agents; D008070:Lipopolysaccharides; D008074:Lipoproteins; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; C069172:2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D003545:Cysteine