G-CSF-mediated inhibition of JNK is a key mechanism for Lactobacillus rhamnosus-induced suppression of TNF production in macrophages

Authors

  • Sung O. Kim,

    Corresponding author
    1. Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
    2. Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
    3. Canadian Research and Development Centre for Probiotics, The Lawson Health Research Institute, London, Ontario, N6A 4V2, Canada.
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  • Haroon I. Sheikh,

    1. Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
    2. Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
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  • Soon-Duck Ha,

    1. Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
    2. Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
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  • Andrew Martins,

    1. Department of Microbiology and Immunology, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
    2. Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
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  • Gregor Reid

    1. Infectious Diseases Research Group, Siebens-Drake Research Institute, University of Western Ontario, London, Ontario, N6G 2V4, Canada.
    2. Canadian Research and Development Centre for Probiotics, The Lawson Health Research Institute, London, Ontario, N6A 4V2, Canada.
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*E-mail skim283@schulich.uwo.ca; Tel. (+1) 519 850 2961; Fax (+1) 519 661 2046.

Summary

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-α (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 STAT3α-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.

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