title: CD40 Signaling in Graves Disease Is Mediated Through Canonical and Noncanonical Thyroidal Nuclear Factor κB Activation.
abstract: CD40, a tumor necrosis factor receptor, is a major immune-modulating susceptibility gene for Graves disease (GD) as well as for a variety of other autoimmune diseases. Its broad association with autoimmunity underscores its paramount role in the development of a normal adaptive immune response, primarily in coordinating effective antigen presentation. The molecular pathways by which CD40 activation in the thyroid induces GD are unknown. In this study, we investigated whether NF-κB, a ubiquitious family of transcription factors, mediates the downstream effects of thyroid-specific CD40 activation. Cultured primary human thyrocytes, from patients with and without GD, underwent CD40 stimulation. Once stimulated, cytokines and transcription factors specific for either the canonical nuclear factor κB (NF-κB)1 pathway [interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α], which primarily recruits cells for innate immunity, or the noncanonical NF-κB2 pathway [B cell-activating factor of the TNF family, CC chemokine ligand (CCL)21], which directs B cell viability, were analyzed. Significant upregulation in the messenger RNA and protein levels of both canonical and noncanonical pathway cytokines was observed. Western blot analyses of the specific transcription factors for the NF-κB1 and NF-κB2 pathways (p65 and p100/p52, respectively) demonstrated that p65 is constitutively expressed. In contrast, CD40 stimulation robustly increased the expression of the NF-κB2 p52 transcription factor, and the upregulation was significantly more profound in the GD tissue than in the normal thyroid tissue. Our data show that CD40 activity in thyrocytes is prominently mediated via NF-κB and furthermore suggest that the NF-κB1 and NF-κB2 pathways both contribute to the triggering and the progression of GD.
authors.affiliation: Division of Endocrinology,  Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
authors.forename: Hanna J
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
authors.forename: Angela
authors.initials: A
authors.lastname: Lombardi
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Stefan
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
authors.forename: Cheuk Wun
authors.initials: CW
authors.lastname: Li
authors.affiliation: Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: William B
authors.initials: WB
authors.lastname: Inabnet
authors.affiliation: Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Randall P
authors.initials: RP
authors.lastname: Owen
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
authors.forename: Erlinda
authors.initials: E
authors.lastname: Concepcion
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York.
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D019013:CD40 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D006111:Graves Disease / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D052002:NF-kappa B p50 Subunit / Q000378:metabolism*; D052003:NF-kappa B p52 Subunit / Q000378:metabolism*; D000072637:Thyroid Epithelial Cells / Q000378:metabolism*
chemical_list: D019013:CD40 Antigens; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit