title: A novel role for the thyroid hormone-activating enzyme type 2 deiodinase in the inflammatory response of macrophages.
abstract: Deiodinase type 2 (D2) is a thyroid hormone-activating enzyme converting the prohormone T4 into the active hormone T3. In the present study, we show for the first time that D2 is up-regulated in the mouse liver during acute and chronic inflammation, in close correlation with the proinflammatory cytokine IL-1β and independently of serum T3. Inflammation-induced D2 expression was confirmed in macrophages, in conjunction with selective thyroid hormone transporter (monocarboxylate transporter 10) and thyroid hormone receptor (TR)α1 stimulation, and was absent in hepatocytes. Moreover, D2 knockdown in macrophages resulted in a clear attenuation of the lipopolysaccharide (LPS)-induced IL-1β and GM-CSF expression, in addition to aberrant phagocytosis. Locally produced T3, acting via the TRα, may be instrumental in this novel inflammatory response, because LPS-treated TRα(0/0) mice showed a markedly decreased LPS-induced GM-CSF mRNA expression. We now propose that hepatic D2 favors the innate immune response by specifically regulating cellular thyroid hormone levels in macrophages.
authors.affiliation: Departments of Endocrinology and Metabolism (J.K., O.V.S., E.M.d.V., A.B., E.F.) and Cell Biology and Histology (J.S.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kwakkel
authors.forename: O V
authors.initials: OV
authors.lastname: Surovtseva
authors.forename: E M
authors.initials: EM
authors.lastname: de Vries
authors.forename: J
authors.initials: J
authors.lastname: Stap
authors.forename: E
authors.initials: E
authors.lastname: Fliers
authors.forename: A
authors.initials: A
authors.lastname: Boelen
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D007453:Iodide Peroxidase / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D037021:Thyroid Hormone Receptors alpha / Q000172:deficiency / Q000235:genetics; D013963:Thyroid Hormones / Q000378:metabolism; D014284:Triiodothyronine / Q000097:blood / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053583:Interleukin-1beta; D007453:Iodide Peroxidase; D008070:Lipopolysaccharides; D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones; D014284:Triiodothyronine; D000097564:Iodothyronine Deiodinase Type II