title: Inhibition of immune activation by a novel nuclear factor-kappa B inhibitor in HTLV-I-associated neurologic disease.
abstract: The human T-lymphotropic virus type I (HTLV-I) causes a chronic inflammatory disorder of the central nervous system termed HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-I encodes a protein known to activate several host-signaling pathways involved in inflammation, such as the nuclear factor-κB (NF-κB). The contribution of the NF-κB pathway to the pathogenesis of HAM/TSP, however, has not been fully defined. We show evidence of canonical NF-κB activation in short-term cultures of peripheral blood mononuclear cells (PBMCs) from subjects with HAM/TSP. NF-κB activation was closely linked to HTLV-I viral protein expression. The NF-κB activation in HAM/TSP PBMCs was reversed by a novel small-molecule inhibitor that demonstrates potent and selective NF-κB antagonist activity. Inhibition of NF-κB activation led to a reduction in the expression of lymphocyte activation markers and resulted in reduced cytokine signaling in HAM/TSP PBMCs. Furthermore, NF-κB inhibition led to a reduction in spontaneous lymphoproliferation, a key ex vivo correlate of the immune activation associated with HAM/TSP. These results indicate that NF-κB activation plays a critical upstream role in the immune activation of HAM/TSP, and identify the NF-κB pathway as a potential target for immunomodulation in HAM/TSP.
authors.affiliation: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Unsong
authors.initials: U
authors.lastname: Oh
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: McCormick
authors.forename: Dibyadeep
authors.initials: D
authors.lastname: Datta
authors.forename: Richard V
authors.initials: RV
authors.lastname: Turner
authors.forename: Kathryn
authors.initials: K
authors.lastname: Bobb
authors.forename: Dileep D
authors.initials: DD
authors.lastname: Monie
authors.forename: D Robert
authors.initials: DR
authors.lastname: Sliskovic
authors.forename: Yuetsu
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Meshulam
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobson
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003512:Cyclohexanones / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006367:HeLa Cells; D015368:Human T-lymphotropic virus 1 / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015493:Paraparesis, Tropical Spastic / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019562:Viral Load / Q000187:drug effects
chemical_list: D001549:Benzamides; D003512:Cyclohexanones; D007155:Immunologic Factors; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin