title: Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease?
abstract: Inflammatory bowel disease is characterized by dysregulated immune responses against intestinal microflora leading to marked activation of nuclear factor-κB (NF-κB) with subsequent production of pro-inflammatory cytokines. Besides NF-κB, the tumor progression locus 2 (TPL-2)/extracellular signal-regulated kinase (ERK) pathway also regulates inflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, but its role during intestinal inflammation is incompletely understood. We analyzed the impact of TPL-2 in the dextran sulfate sodium-induced experimental colitis model. Despite normal activation of NF-κB, animals lacking TPL-2 developed only mild colitis with reduced synthesis of inflammatory cytokines. Further, pharmacological inhibition of the TPL-2 kinase was similarly effective in ameliorating colitis as TPL-2 deficiency without obvious side effects. Because increased TPL-2/ERK activation was seen in patients with Crohn's disease (CD) but not ulcerative colitis, our findings encourage further investigation of TPL-2 kinase as potential target for the treatment of CD patients.
authors.affiliation: Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Lawrenz
authors.forename: A
authors.initials: A
authors.lastname: Visekruna
authors.forename: A
authors.initials: A
authors.lastname: Kühl
authors.forename: N
authors.initials: N
authors.lastname: Schmidt
authors.forename: S H E
authors.initials: SH
authors.lastname: Kaufmann
authors.forename: U
authors.initials: U
authors.lastname: Steinhoff
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D003424:Crohn Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D016264:Dextran Sulfate; D020930:MAP Kinase Kinase Kinases; C489843:Map3k8 protein, mouse