title: Essential role of JAK/STAT pathway in the induction of cell cycle arrest in macrophages infected with periodontopathic bacterium Aggregatibacter actinomycetemcomitans.
abstract: In the present study, phosphorylation of signal transducers and activators of transcription 3 (STAT3) was found to be important in the induction of G1 cell cycle arrest in murine macrophages infected with Aggregatibacter actinomycetemcomitans. First, we focused on suppressor of cytokine signaling 3 (SOCS3) as a negative regulator of the JAK/STAT pathway. Flow cytometric analysis showed that A. actinomycetemcomitans infection eliminated G1 cell cycle arrest in SOCS3-overexpressing RAW 264.7 macrophage cells. Western blotting analysis demonstrated expression of cell cycle-associated protein p21 and hypophosphorylation of retinoblastoma protein (Rb) was decreased in SOCS3-overexpressing RAW 264.7 cells. AG490, a specific inhibitor of JAK2, inhibited the expression of p21 and degradation of cyclin D1 in A. actinomycetemcomitans-infected RAW 264.7 cells, resulting in suppression of STAT3 phosphorylation. These results indicated that constitutive SOCS3 expression and AG490 inhibited the expression of JAK2 and phosphorylation of STAT3, and prevented cell cycle arrest in A. actinomycetemcomitans-infected RAW 264.7 cells. These findings suggest that the JAK/STAT pathway plays crucial roles in the cell cycle regulation of macrophages infected with periodontopathic bacteria through the suppression of p21 expression and degradation of cyclin D1.
authors.affiliation: Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental College, Kokurakita-ku, Kitakyushu, Japan.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Okinaga
authors.forename: Wataru
authors.initials: W
authors.lastname: Ariyoshi
authors.forename: Sumio
authors.initials: S
authors.lastname: Akifusa
authors.forename: Tatsuji
authors.initials: T
authors.lastname: Nishihara
mesh_terms: D000189:Actinobacillus Infections / Q000276:immunology / Q000378:metabolism*; D016976:Aggregatibacter actinomycetemcomitans / Q000502:physiology*; D000818:Animals; D059447:Cell Cycle Checkpoints; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D015870:Gene Expression; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053614:Janus Kinase 2; D053612:Janus Kinases