title: Nuclear factor (NF)-kappaB-dependent thyroid hormone receptor beta1 expression controls dendritic cell function via Akt signaling.
abstract: Despite considerable progress in our understanding of the interplay between immune and endocrine systems, the role of thyroid hormones and their receptors in the control of adaptive immunity is still uncertain. Here, we investigated the role of thyroid hormone receptor (TR) beta(1) signaling in modulating dendritic cell (DC) physiology and the intracellular mechanisms underlying these immunoregulatory effects. Exposure of DCs to triiodothyronine (T(3)) resulted in a rapid and sustained increase in Akt phosphorylation independently of phosphatidylinositol 3-kinase activation, which was essential for supporting T(3)-induced DC maturation and interleukin (IL)-12 production. This effect was dependent on intact TR beta(1) signaling as small interfering RNA-mediated silencing of TR beta(1) expression prevented T(3)-induced DC maturation and IL-12 secretion as well as Akt activation and I kappaB-epsilon degradation. In turn, T(3) up-regulated TR beta(1) expression through mechanisms involving NF-kappaB, suggesting an autocrine regulatory loop to control hormone-dependent TR beta(1) signaling. These findings were confirmed by chromatin immunoprecipitation analysis, which disclosed a new functional NF-kappaB consensus site in the promoter region of the TRB1 gene. Thus, a T(3)-induced NF-kappaB-dependent mechanism controls TR beta(1) expression, which in turn signals DCs to promote maturation and function via an Akt-dependent but PI3K-independent pathway. These results underscore a novel unrecognized target that regulates DC maturation and function with critical implications in immunopathology at the cross-roads of the immune-endocrine circuits.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba.
authors.forename: Iván D
authors.initials: ID
authors.lastname: Mascanfroni
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba.
authors.forename: María
authors.initials: M
authors.lastname: Del Mar Montesinos
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba.
authors.forename: Vanina A
authors.initials: VA
authors.lastname: Alamino
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Susperreguy
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Nicola
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428 Ciudad de Buenos Aires, C1428 Ciudad de Buenos Aires, Argentina.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Ilarregui
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Masini-Repiso
authors.affiliation: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental, Consejo Nacional de Investigaciones Científicas y Técnicas, C1428 Ciudad de Buenos Aires, C1428 Ciudad de Buenos Aires, Argentina; Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, C1428 Ciudad de Buenos Aires, Argentina.
authors.forename: Gabriel A
authors.initials: GA
authors.lastname: Rabinovich
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, 5000 Córdoba. Electronic address: claudia@fcq.unc.edu.ar.
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Pellizas
mesh_terms: D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D015151:Immunoblotting; D018664:Interleukin-12 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D037042:Thyroid Hormone Receptors beta / Q000378:metabolism*; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D034741:RNA, Small Interfering; D037042:Thyroid Hormone Receptors beta; D014284:Triiodothyronine; D018664:Interleukin-12; D051057:Proto-Oncogene Proteins c-akt