Present address: University of Colorado Health Sciences Center, Denver, CO, USA;
The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls
Article first published online: 28 JUN 2008
© 2008 The Authors. Journal compilation © 2008 Blackwell Publishing Ltd
Volume 10, Issue 10, pages 2067–2077, October 2008
How to Cite
Moreira, L. O., El Kasmi, K. C., Smith, A. M., Finkelstein, D., Fillon, S., Kim, Y.-G., Núñez, G., Tuomanen, E. and Murray, P. J. (2008), The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls. Cellular Microbiology, 10: 2067–2077. doi: 10.1111/j.1462-5822.2008.01189.x
- Issue published online: 8 SEP 2008
- Article first published online: 28 JUN 2008
- Received 2 May, 2008; revised 31 May, 2008; accepted 2 June, 2008.
Systemic infection with Streptococcus pneumoniae is associated with a vigorous pro-inflammatory response to structurally complex cell wall fragments (PnCW) that are shed during cell growth and antibiotic-induced autolysis. Consistent with previous studies, inflammatory cytokine production induced by PnCW was dependent on TLR2 but independent of NOD2, a cytoplasmic NLR protein. However, in parallel with the pro-inflammatory response, we found that PnCW also induced prodigious secretion of anti-inflammatory IL-10 from macrophages. This response was dependent on TLR2, but also involved NOD2 as absence of NOD2-reduced IL-10 secretion in response to cell wall and translated into diminished downstream effects on IL-10-regulated target gene expression. PnCW-mediated production of IL-10 via TLR2 required RIPK2 a kinase required for NOD2 function, and MyD88 but differed from that known for zymosan in that ERK pathway activation was not detected. As mutations in NOD2 are linked to aberrant immune responses, the temporal and quantitative effects of activation of the TLR2-NOD2-RIPK2 pathway on IL-10 secretion may affect the balance between pro- and anti-inflammatory responses to Gram-positive bacteria.