Anti-inflammatory actions of probiotics through activating suppressor of cytokine signaling (SOCS) expression and signaling in Helicobacter pylori infection: a novel mechanism.
OBJECTIVE
In spite of the International Agency for Research on Cancer's definition that Helicobacter pylori is the definite carcinogen of gastric cancer, the simple eradication of the bug is not enough to prevent resultant gastric cancer, and increasing microbial resistance further limits the eradication application. Therefore, probiotics, non-pathogenic microbial feed that can affect the host in a beneficial manner, could be an alternate way to enhance anti-inflammation against H. pylori. However, the mechanism of their anti-inflammatory actions is still unclear. In the current study, we hypothesized that suppressor of cytokine signaling (SOCS) signaling could be a feasible anti-inflammatory mechanism of probiotics against H. pylori infection.


RESULTS
H. pylori infection or their lipopolysaccharide stimulation led to significant increased expressions of inflammatory mediators including tumor necrosis factor-alpha, interleukin-8, inducible nitric oxide synthase and cyclooxygenase-2 in AGS cells and pretreatment of Lactobacillus plantarum, Lactobacillus rhamnosis and Lactobacillus acidophilus significantly attenuated the expressions of these inflammatory mediators in accordance with the blocking action of nuclear factor-kappaB nuclear translocation. Probiotic administration increased expression of SOCS-2 and SOCS-3 and exerted the active SOCS signaling featured with earlier and higher expressions of SOCS-2 and SOCS-3. In contrast to weak inactivation of mitogen-activated protein kinases including p-38 and extracellular signal-regulated kinase 1/2, probiotic-induced SOCS expressions were mediated through either significant phosphorylation of signal transducers and activation of transcription (STAT)-1 and STAT-3 or simultaneous inhibition of Janus kinase (JAK)2 phosphorylation, which is known to signal SOCS-2/SOCS-3 negatively.


CONCLUSIONS
Anti-inflammatory signals of SOCS through STAT-1/STAT-3 activation and JAK2 inactivation might be a key anti-inflammatory mechanism of probiotics, setting probiotics as a non-microbial strategy to H. pylori infection.
Laboratory of Translational Medicine, Gachon University Lee Gil Ya Cancer and Diabetes Institute, Department of Gastroenterology, Gachon Graduate School of Medicine, Incheon, Korea.
Jeong Sang
JS
Lee
Nam Soo
NS
Paek
Oh Sang
OS
Kwon
Ki Baik
KB
Hahm
D045744:Cell Line, Tumor; D005753:Gastric Mucosa / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D005756:Gastritis / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000517:prevention & control*; D016481:Helicobacter Infections / Q000276:immunology / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism; D007779:Lactobacillus acidophilus / Q000254:growth & development; D048191:Lactiplantibacillus plantarum / Q000254:growth & development; D052201:Lacticaseibacillus rhamnosus / Q000254:growth & development; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D019936:Probiotics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism*; D013997:Time Factors
D018836:Inflammation Mediators; D016328:NF-kappa B; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D020928:Mitogen-Activated Protein Kinases