TLR4-dependent NF-kappaB activation and mitogen- and stress-activated protein kinase 1-triggered phosphorylation events are central to Helicobacter pylori peptidyl prolyl cis-, trans-isomerase (HP0175)-mediated induction of IL-6 release from macrophages.
Helicobacter pylori infection is associated with the local production of chemokines and cytokines, of which IL-6 is overexpressed at the margin of gastric ulcer in H. pylori-positive gastritis. Cells of the monocytic lineage are the major sources of IL-6, and mononuclear cell infiltration in the lamina propria is characteristic of H. pylori-induced chronic infection. Our study shows for the first time that a secreted peptidyl prolyl cis-, trans-isomerase, HP0175 elicits IL-6 gene expression and IL-6 release from macrophages. An isogenic strain inactivated in the HP0175 gene (knockout) was attenuated in its IL-6-inducing ability, which was restored after complementation with the HP0175 gene. The specificity of the HP0175-induced effect was confirmed by the fact that rHP0175 purified from HEK293 cells could also induce IL-6 release, ruling out the possibility that the observed effect was due to bacterial contaminants. HP0175 was capable of interacting directly with the extracellular domain of TLR4. HP0175-induced IL-6 gene expression was critically dependent on TLR4-dependent NF-kappaB and MAPK activation. TLR4/PI3K-dependent ERK1/2 and p38 MAPK signaling converged upon activation of mitogen- and stress-activated protein kinase 1 (MSK1). The central role of MSK1 was borne out by the fact that silencing of MSK1 expression abrogated HP0175-mediated NF-kappaB-dependent IL-6 gene transcription. MSK1 regulated the recruitment of p65 and phopho-Ser(10)-histone H3 to the IL-6 promoter. HP0175 therefore regulated IL-6 gene transcription through chromatin modification at the IL-6 promoter.
Pathak
Sushil Kumar
SK
Department of Chemistry, Bose Institute, 93/1 Acharya Prafulla, Chandra Road, Kolkata 700009, India.
Basu
Sanchita
S
Bhattacharyya
Asima
A
Pathak
Shresh
S
Banerjee
Anirban
A
Basu
Joyoti
J
Kundu
Manikuntala
M
D015153:Blotting, Western; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression; D016480:Helicobacter pylori / Q000201:enzymology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000276:immunology / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8 / Q000276:immunology / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism*; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D019696:Peptidylprolyl Isomerase