title: Inhibition of IL-17 as a pharmacological approach for IBD.
abstract: Several experimental approaches have been utilized, in order to critically examine the roles of IL-17 family members in intestinal inflammation. These approaches have included: (1) the use of IL-17A and IL-17F-deficient mice, (2) specific antibodies directed against IL-17, (3) an IL-17 vaccine, (4) methods to block the IL-17 receptor and (5) small-molecule inhibitors of IL-17. Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease (IBD), using specific strains of IL-17-deficient mice. This paper will review the preclinical results using various pharmacological approaches [specific IL-17 antibodies, an IL-17 receptor fusion protein, IL-12/IL-23 p40 subunit and IL-17 vaccine approaches, as well as a small molecule inhibitor (Vidofludimus)] to inhibit IL-17 in animal models of IBD. Recent clinical results in patients with IBD will also be discussed for Secukinumab (an IL-17A antibody), Brodalumab (an IL-17 receptor antibody) and two small-molecule drugs (Vidofludimus and Tofacitinib), which inhibit IL-17 as part of their overall pharmacological profiles. This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti-IL-17 drugs, as related to drug pharmacodynamics, IL-17 receptor subtypes and other pertinent factors. Finally, future pharmacological approaches of interest will be discussed, such as: (1) Retinoic acid receptor-related orphan nuclear receptor gamma t (Rorγt) antagonists, (2) Retinoic acid receptor alpha (RARα) antagonists, (3) Pim-1 kinase inhibitors and (4) Dual small-molecule inhibitors of NF-κB and STAT3, like synthetic triterpenoids.
authors.affiliation: Department of Pharmacology, Penn State College of Medicine , Hummelstown, Pennsylvania , USA.
authors.forename: Leo R
authors.initials: LR
authors.lastname: Fitzpatrick
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D020381:Interleukin-17