Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti-inflammatory IL-22 and IL-10 response.
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.
Division of Laboratory Medicine, Department of MIG, Lund University, Lund, Sweden.
Nataliya
N
Lutay
Division of Laboratory Medicine, Department of MIG, Lund University, Lund, Sweden.
Gisela
G
Håkansson
Division of Laboratory Medicine, Department of MIG, Lund University, Lund, Sweden.
Nader
N
Alaridah
Division of Clinical Sciences, Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden.
Oskar
O
Hallgren
Division of Vascular- and Respiratory Research Unit of Lung Biology, Department of Experimental Medical Science, Lund University, Lund, Sweden.
Gunilla
G
Westergren-Thorsson
Division of Laboratory Medicine, Department of MIG, Lund University, Lund, Sweden.
Gabriela
G
Godaly
D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000382:microbiology* / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000382:microbiology*; D016753:Interleukin-10 / Q000378:metabolism*; D007378:Interleukins / Q000378:metabolism*; D009092:Mucous Membrane / Q000378:metabolism* / Q000473:pathology; D009163:Mycobacterium bovis / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism*; D066329:Protein Aggregates; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism; D000097043:Interleukin-22
D017362:Cyclic AMP Response Element-Binding Protein; D016207:Cytokines; D048049:Extracellular Signal-Regulated MAP Kinases; D038362:Glycogen Synthase Kinase 3; D016753:Interleukin-10; D007378:Interleukins; D016328:NF-kappa B; D066329:Protein Aggregates; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D051193:Toll-Like Receptors; D000097043:Interleukin-22