title: JAK inhibition using tofacitinib for inflammatory bowel disease treatment: a hub for multiple inflammatory cytokines.
abstract: The inflammatory diseases ulcerative colitis and Crohn's disease constitute the two main forms of inflammatory bowel disease (IBD). They are characterized by chronic, relapsing inflammation of the gastrointestinal tract, significantly impacting on patient quality of life and often requiring prolonged treatment. Existing therapies for IBD are not effective for all patients, and an unmet need exists for additional therapies to induce and maintain remission. Here we describe the mechanism of action of the Janus kinase (JAK) inhibitor, tofacitinib, for the treatment of IBD and the effect of JAK inhibition on the chronic cycle of inflammation that is characteristic of the disease. The pathogenesis of IBD involves a dysfunctional response from the innate and adaptive immune system, resulting in overexpression of multiple inflammatory cytokines, many of which signal through JAKs. Thus JAK inhibition allows multiple cytokine signaling pathways to be targeted and is expected to modulate the innate and adaptive immune response in IBD, thereby interrupting the cycle of inflammation. Tofacitinib is an oral, small molecule JAK inhibitor that is being investigated as a targeted immunomodulator for IBD. Clinical development of tofacitinib and other JAK inhibitors is ongoing, with the aspiration of providing new treatment options for IBD that have the potential to deliver prolonged efficacy and clinically meaningful patient benefits.
authors.affiliation: Division of Gastroenterology, Inflammatory Bowel Disease Center and Humanities Medical School, Milan, Italy; sdanese@hotmail.com.
authors.forename: Silvio
authors.initials: S
authors.lastname: Danese
authors.affiliation: Department of Immunology and Molecular Microbiology, Texas Tech University Health Sciences Center, Lubbock, Texas;
authors.forename: Matthew
authors.initials: M
authors.lastname: Grisham
authors.affiliation: Pfizer Inc., New York, New York; and.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hodge
authors.affiliation: Pfizer Inc., Cambridge, Massachusetts.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Telliez
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D010880:Piperidines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016207:Cytokines; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053612:Janus Kinases
keywords: Crohn's disease; inflammation; inflammatory bowel disease; ulcerative colitis