title: The role of PIM kinases in human and mouse CD4+ T cell activation and inflammatory bowel disease.
abstract: PIM kinases are a family of three serine/threonine kinases expressed following T cell activation. Using potent selective small molecule antagonists of PIM-1/3 kinases, we demonstrate a potential role for these enzymes in naïve and effector CD4+ T cell activation. PIM-1/3 inhibition prevented CD4+ T cell proliferation by inducing a G0/G1 cell cycle arrest without affecting cellular survival. In the absence of PIM-1/3 kinase activity, naïve CD4+ T cells failed to fully differentiate into effector cells both in vitro and in vivo. Therapeutic dosing of a PIM-1/3 inhibitor was efficacious in a CD4+ T cell-mediated model of inflammatory bowel disease suggesting that PIM-1 and PIM-3 kinase activity contributes to sustained disease severity. These results demonstrate that PIM-1/3 kinases have an important role in CD4+ T cell responses and inhibition of this activity may provide a therapeutic benefit in T cell-mediated diseases.
authors.affiliation: Department of Cell Biology, Array BioPharma, Boulder, CO 80301, United States. leilajjackson@gmail.com
authors.forename: Leila J
authors.initials: LJ
authors.lastname: Jackson
authors.forename: Jed A
authors.initials: JA
authors.lastname: Pheneger
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Pheneger
authors.forename: Gregg
authors.initials: G
authors.lastname: Davis
authors.forename: A Dale
authors.initials: AD
authors.lastname: Wright
authors.forename: John E
authors.initials: JE
authors.lastname: Robinson
authors.forename: Shelley
authors.initials: S
authors.lastname: Allen
authors.forename: Mark C
authors.initials: MC
authors.lastname: Munson
authors.forename: Laura L
authors.initials: LL
authors.lastname: Carter
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D053612:Janus Kinases / Q000378:metabolism; D008213:Lymphocyte Activation; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D016207:Cytokines; D047428:Protein Kinase Inhibitors; D053612:Janus Kinases; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases