G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages.
Lactobacillus rhamnosus is a human commensal with known immunomodulatory properties. To date the mechanism of these immunomodulatory effects is not well understood. To unravel the immunomodulatory signalling mechanism, we investigated the effects of two strains of L. rhamnosus, L. rhamnosus GG and GR-1, in modulating production of tumour necrosis factor-alpha (TNF) in human monocytic cell line THP-1 and mouse macrophages. Live L. rhamnosus GG and GR-1 or their spent culture supernatant induced minuscule amounts of TNF production but large quantities of granulocyte-colony stimulating factor (G-CSF) in macrophages compared with those induced by pathogenic Escherichia coli GR-12 and Enterococcus faecalis. By using neutralizing antibodies and G-CSF receptor knockout mice, we demonstrated that G-CSF secreted from L. rhamnosus GG- and GR-1-exposed macrophages suppressed TNF production induced by E. coli- or lipopolysaccharide-activated macrophages through a paracrine route. The suppression of TNF production by G-CSF was mediated through activation of STAT3 and subsequent inhibition of c-Jun-N-terminal kinases (JNKs). The inhibition of JNK activation required STAT3alpha-mediated de novo protein synthesis. This demonstrates a novel role of G-CSF in L. rhamnosus-triggered anti-inflammatory effects and its mechanism in the suppression of TNF production in macrophages.
Kim
Sung O
SO
Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, N6G 2V4, Canada. skim283@schulich.uwo.ca
Sheikh
Haroon I
HI
Ha
Soon-Duck
SD
Martins
Andrew
A
Reid
Gregor
G
D000818:Animals; D001854:Bone Marrow Cells; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D013293:Enterococcus faecalis / Q000472:pathogenicity; D004926:Escherichia coli / Q000472:pathogenicity; D016179:Granulocyte Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D052201:Lacticaseibacillus rhamnosus / Q000276:immunology*; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D019936:Probiotics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D016207:Cytokines; D050796:STAT3 Transcription Factor; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases