title: Porphyromonas gingivalis-induced reactive oxygen species activate JAK2 and regulate production of inflammatory cytokines through c-Jun.
abstract: Pathogen-induced reactive oxygen species (ROS) play a crucial role in host innate immune responses through regulating the quality and quantity of inflammatory mediators. However, the underlying molecular mechanisms of this effect have yet to be clarified. In this study, we examined the mechanism of action of ROS stimulated by Porphyromonas gingivalis in gingival epithelial cells. P. gingivalis induced the rapid production of ROS, which lead to the phosphorylation of JAK2 and increased levels of secreted proinflammatory cytokines interleukin-6 (IL-6) and IL-1β. Neutralization of ROS by N-acetyl-l-cysteine (NAC) abrogated the phosphorylation of JAK2 and suppressed the production of IL-6 and IL-1β. ROS-mediated phosphorylation of JAK2 induced the phosphoactivation of c-Jun amino-terminal protein kinase (JNK) and the downstream transcriptional regulator c-Jun. Inhibition of JAK2, either pharmacologically or by small interfering RNA (siRNA), reduced both the phosphorylation of these molecules and the production of proinflammatory cytokines in response to P. gingivalis. Furthermore, pharmacological inhibition or siRNA-mediated gene silencing of JNK or c-Jun mimicked the effect of JAK2 inhibition to suppress P. gingivalis-induced IL-6 and IL-1β levels. The results show that ROS-mediated activation of JAK2 is required for P. gingivalis-induced inflammatory cytokine production and that the JNK/c-Jun signaling axis is involved in the ROS-dependent regulation of IL-1β and IL-6 production.
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA hhwang01@louisville.edu rich.lamont@louisville.edu.
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Huaxin
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Xiaoxian
authors.initials: X
authors.lastname: Duan
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Jotwani
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Himabindu
authors.initials: H
authors.lastname: Vuddaraju
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, Kentucky, USA hhwang01@louisville.edu rich.lamont@louisville.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
mesh_terms: D002478:Cells, Cultured; D004847:Epithelial Cells / Q000276:immunology* / Q000382:microbiology; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis*; D015850:Interleukin-6 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D010766:Phosphorylation; D016966:Porphyromonas gingivalis / Q000276:immunology*; D011499:Protein Processing, Post-Translational; D017382:Reactive Oxygen Species / Q000633:toxicity*
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D017382:Reactive Oxygen Species; C507924:JAK2 protein, human; D053614:Janus Kinase 2; D048031:JNK Mitogen-Activated Protein Kinases