title: Treatment of mice with the suppressor of cytokine signaling-1 mimetic peptide, tyrosine kinase inhibitor peptide, prevents development of the acute form of experimental allergic encephalomyelitis and induces stable remission in the chronic relapsing/remitting form.
abstract: We have previously characterized a novel tyrosine kinase inhibitor peptide (Tkip) that is a mimetic of suppressor of cytokine signaling 1 (SOCS-1) and inhibits JAK2 phosphorylation of the transcription factor STAT1alpha. We show in this study that Tkip protects mice against experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis. Mice are immunized with myelin basic protein (MBP) for induction of disease. Tkip (63 mug) administered every other day suppressed the development of acute EAE in 75% of New Zealand White (NZW) mice. Furthermore, Tkip completely protected SJL/J mice, which where induced to get the relapsing/remitting form of EAE, against relapses compared with control groups in which >70% of the mice relapsed after primary incidence of disease. Protection of mice by Tkip was similar to that seen with the type I IFN, IFN-tau. Protection of mice correlated with lower MBP Ab titers in Tkip-treated groups as well as suppression of MBP-induced proliferation of splenocytes taken from EAE-afflicted mice. Cessation of Tkip and IFN-tau administration resulted in SJL/J mice relapsing back into disease. Prolonged treatment of mice with Tkip produced no evidence of cellular toxicity or weight loss. Consistent with its JAK2 inhibitory function, Tkip also inhibited the activity of the inflammatory cytokine TNF-alpha, which uses the STAT1alpha transcription factor. The data presented in this study show that Tkip, like the type I IFN, IFN-tau, inhibits both the autoreactive cellular and humoral responses in EAE and ameliorates both the acute and chronic relapsing/remitting forms of EAE.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611, USA. mgm2@ufl.edu
authors.forename: Mustafa G
authors.initials: MG
authors.lastname: Mujtaba
authors.forename: Lawrence O
authors.initials: LO
authors.lastname: Flowers
authors.forename: Chintak B
authors.initials: CB
authors.lastname: Patel
authors.forename: Ravi A
authors.initials: RA
authors.lastname: Patel
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Haider
authors.forename: Howard M
authors.initials: HM
authors.lastname: Johnson
mesh_terms: D000208:Acute Disease; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control*; D050832:Interferon-Stimulated Gene Factor 3 / Q000037:antagonists & inhibitors; D007371:Interferon-gamma / Q000008:administration & dosage* / Q000138:chemical synthesis; D051379:Mice; D008814:Mice, Inbred NZB; D018716:Molecular Mimicry / Q000276:immunology; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000138:chemical synthesis; D010455:Peptides / Q000008:administration & dosage* / Q000138:chemical synthesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D012008:Recurrence; D012097:Repressor Proteins / Q000502:physiology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D050832:Interferon-Stimulated Gene Factor 3; D010446:Peptide Fragments; D010455:Peptides; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014409:Tumor Necrosis Factor-alpha; C079868:gamma interferon activation factor; C104514:interferon-gamma (95-133); C061479:protein kinase inhibitor peptide; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases