title: Intra-articular nuclear factor-κB blockade ameliorates collagen-induced arthritis in mice by eliciting regulatory T cells and macrophages.
abstract: Nuclear factor (NF)-κB is a transcription factor implicated in the pathogenesis of autoimmune disorders such as rheumatoid arthritis (RA). Here we have examined the effect of intra-articular administration of the IKK inhibitor, NEMO-binding domain peptide (NBD), on the severity of collagen-induced arthritis (CIA). NBD peptides were injected intra-articularly into the knee joints of DBA/1J mice after the onset of disease. Collagen-injected mice given a scrambled peptide served as controls. Arthritis severity was determined by visual examination of paws. Intra-articular NBD injection reduced the arthritis score and ameliorated morphological signs of bone destruction compared to the controls. Serum levels of type-II collagen-specific immunoglobulin (Ig)G2a antibodies were lower in NBD-treated mice versus the control mice, whereas the levels of type-II collagen-specific IgG1 antibodies were increased by NBD treatment. NBD treatment diminished the proinflammatory cytokines interleukin (IL)-17 and interferon (IFN)-γ in serum, but increased the regulatory cytokine IL-10. NBD-treated CIA mice exhibited significantly higher percentages and numbers of forkhead box protein 3 (FoxP3(+)) CD4(+) CD25(+) regulatory T cells than controls. Immunofluorescence analysis of NBD-treated mice revealed that FoxP3 and Ym1, a marker of alternatively activated macrophages, were juxtaposed to each other within draining inguinal lymph nodes. Intra-articular administration of NBD peptide is effective as an experimental therapy in a murine model of RA. Nevertheless, the intra-articular treatment modality is still associated with systemic effects on the immune system.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Min
authors.forename: M
authors.initials: M
authors.lastname: Yan
authors.forename: Y
authors.initials: Y
authors.lastname: Du
authors.forename: T
authors.initials: T
authors.lastname: Wu
authors.forename: E
authors.initials: E
authors.lastname: Khobahy
authors.forename: S-R
authors.initials: SR
authors.lastname: Kwon
authors.forename: V
authors.initials: V
authors.lastname: Taneja
authors.forename: A
authors.initials: A
authors.lastname: Bashmakov
authors.forename: S
authors.initials: S
authors.lastname: Nukala
authors.forename: Y
authors.initials: Y
authors.lastname: Ye
authors.forename: J
authors.initials: J
authors.lastname: Orme
authors.forename: D
authors.initials: D
authors.lastname: Sajitharan
authors.forename: H-Y
authors.initials: HY
authors.lastname: Kim
authors.forename: C
authors.initials: C
authors.lastname: Mohan
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity; D015704:CD4 Antigens / Q000096:biosynthesis; D003094:Collagen; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D020381:Interleukin-17 / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D037102:Lectins; D008213:Lymphocyte Activation; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D001619:beta-N-Acetylhexosaminidases
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007074:Immunoglobulin G; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D037102:Lectins; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D016753:Interleukin-10; D007371:Interferon-gamma; D003094:Collagen; C429541:Chil3 protein, mouse; D001619:beta-N-Acetylhexosaminidases