Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti-inflammatory IL-22 and IL-10 response

PLoS One. 2014 Jan 28;9(1):e86466. doi: 10.1371/journal.pone.0086466. eCollection 2014.

Abstract

The mechanisms by which mycobacteria subvert the inflammatory defence to establish chronic infection remain an unresolved question in the pathogenesis of tuberculosis. Using primary epithelial cells, we have analysed mycobacteria induced epithelial signalling pathways from activation of TLRs to cytokine secretion. Mycobacterium bovis bacilli Calmette-Guerin induced phosphorylation of glycogen synthase kinase (GSK)3 by PI3K-Akt in the signalling pathway downstream of TLR2 and TLR4. Mycobacteria did not suppress NF-κB by activating the peroxisome proliferator-activated receptor γ. Instead the pro-inflammatory NF-κB was bypassed by mycobacteria induced GSK3 inhibition that promoted the anti-inflammatory transcription factor CREB. Mycobacterial infection did not thus induce mucosal pro-inflammatory response as measured by TNFα and IFNγ secretion, but led to an anti-inflammatory IL-10 and IL-22 production. Apart from CREB, MAP3Ks p38 and ERK1/2 activated the transcription factor AP-1 leading to IL-6 production. Interestingly, blocking of TLR4 before infection decreased epithelial IL-6 secretion, but increased the CREB-activated IL-10 production. Our data indicate that mycobacteria suppress epithelial pro-inflammatory production by suppressing NF-κB activation thereby shifting the infection towards an anti-inflammatory state. This balance between the host immune response and the pathogen could determine the outcome of infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cytokines / biosynthesis
  • Cytoplasm / metabolism
  • Epithelial Cells / enzymology
  • Epithelial Cells / microbiology*
  • Epithelial Cells / pathology*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Inflammation / microbiology*
  • Interleukin-10 / metabolism*
  • Interleukin-22
  • Interleukins / metabolism*
  • Mucous Membrane / metabolism*
  • Mucous Membrane / pathology
  • Mycobacterium bovis / physiology*
  • NF-kappa B / metabolism*
  • Protein Aggregates
  • Proto-Oncogene Proteins c-fos / metabolism
  • Proto-Oncogene Proteins c-jun / metabolism
  • Signal Transduction
  • Toll-Like Receptors / metabolism

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Cytokines
  • Interleukins
  • NF-kappa B
  • Protein Aggregates
  • Proto-Oncogene Proteins c-fos
  • Proto-Oncogene Proteins c-jun
  • Toll-Like Receptors
  • Interleukin-10
  • Extracellular Signal-Regulated MAP Kinases
  • Glycogen Synthase Kinase 3

Grants and funding

This study was supported by a Research Scientist Grant from the Swedish Medical Research Council (2005-7364, 7364, 11550); the Crafoord Foundation; the Heart and Lung Foundation; Evy and Gunnar Sandberg Foundation and the Medical Faculty of Lund University, Sweden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.