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l-]} l-]} l-] } l-] P}l-] }l-] }l-] }l-]  }l-]  `}l-]}l-]}l-]}l-] }l-] p}" dd } dd }" dd@} dd`}dd}" dd } dd }" dd@} dd`}dd ld(    Z$0z   zFClick to edit the title text format$ $  Z0z ,  Click to edit the outline text format Second Outline Level Third Outline Level Fourth Outline Level Fifth Outline Level Sixth Outline Level Seventh Outline Level Eighth Outline Level Ninth Outline Level6& N  6qљYs ? ̙33L   (    Z1z z6     Zd2z  81  H  0޽h ? ̙33 %  0 (     T2z ? ) 4Figure 2 Thyroid hormone induces a pro-inflammatory response in macrophages. .Nl-]N N 6 X  x @`j  BA ?1mj  BA ?'p  T$3z ?3'  pAnne H van der Spek et al. J Endocrinol 2017;232:R67-R81,9l-]9  9 X J  T3z ?D Z @ 2017 Society for Endocrinology*!l-]!  ! & X  x 6N  6qљYs ? ̙33ZR___PPT102.]0G+D' = @B D' = @BA?%,( < +O%,( < ++ 5 @$(  @  C ?z7   T3z ? 9=   Thyroid hormone induces a pro-inflammatory response in macrophages. (A) The effects of TH in macrophages are mediated through integrin v3 or through modulation of intracellular TH levels. TH can bind to integrin v3 on the macrophage cell surface resulting in the activation of PI3K and ERK1/2 pathways followed by the upregulation of inducible nitric oxide synthase (iNOS) (Chen et al. 2012). Alternatively, TH can enter the cell through TH transporters MCT8 or MCT10 after which the prohormone T4 is converted to active hormone T3 by type 2 deiodinase (D2) resulting in increased phagocytosis and cytokine response. D2 is induced in lipopolysaccharide (LPS)-stimulated macrophages (Kwakkel et al. 2014). The effects of intracellular T3 are partly mediated via TR, which is required for adequate macrophage function (Billon et al. 2014, Kwakkel et al. 2014). Low-grade inflammation found in unstimulated TR-knockout macrophages suggests that TR possibly attenuates the rapid pro-inflammatory response generated by increased intracellular TH levels (Billon et al. 2014). (B) Kupffer cells are the resident macrophages of the liver. TH stimulation in vivo results in Kupffer cell hyperplasia and enhanced phagocytosis (Tapia et al. 1997, Valencia et al. 2004). TH transporter and receptor expression in Kupffer cells have not yet been studied. TH also increases the production of TNF by Kupffer cells (Valencia et al. 2004, Fernandez et al. 2005, 2007b). TNF produced by Kupffer cells results in liver NFB activation (Valencia et al. 2004). IL-6 production is also increased, resulting in increased STAT3 activation (Tapia et al. 2006). 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