A novel anti-mycobacterial function of mitogen-activated protein kinase phosphatase-1

BMC Immunol. 2009 Dec 17;10:64. doi: 10.1186/1471-2172-10-64.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Cysteine / analogs & derivatives
  • Cysteine / pharmacology
  • Dual Specificity Phosphatase 1 / physiology*
  • Enzyme Induction
  • Humans
  • Lipopolysaccharides / pharmacology
  • Lipoproteins / pharmacology
  • Mitogen-Activated Protein Kinase 1 / physiology
  • Mitogen-Activated Protein Kinase 3 / physiology
  • Monocytes / physiology
  • Mycobacterium bovis / physiology*
  • RNA, Small Interfering / pharmacology
  • Transfection
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / physiology
  • p38 Mitogen-Activated Protein Kinases / physiology

Substances

  • Anti-Bacterial Agents
  • Lipopolysaccharides
  • Lipoproteins
  • RNA, Small Interfering
  • Tumor Necrosis Factor-alpha
  • 2,3-bis(palmitoyloxy)-2-propyl-1-palmitoylcysteine
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • p38 Mitogen-Activated Protein Kinases
  • DUSP1 protein, human
  • Dual Specificity Phosphatase 1
  • Cysteine