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      TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages.

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          Abstract

          Sensors of pathogens, such as Toll-like receptors (TLRs), detect microbes to activate transcriptional programs that orchestrate adaptive responses to specific insults. Here we report that TLR4 and TLR2 specifically activated the endoplasmic reticulum (ER) stress sensor kinase IRE1alpha and its downstream target, the transcription factor XBP1. Previously described ER-stress target genes of XBP1 were not induced by TLR signaling. Instead, TLR-activated XBP1 was required for optimal and sustained production of proinflammatory cytokines in macrophages. Consistent with that finding, activation of IRE1alpha by ER stress acted in synergy with TLR activation for cytokine production. Moreover, XBP1 deficiency resulted in a much greater bacterial burden in mice infected with the TLR2-activating human intracellular pathogen Francisella tularensis. Our findings identify an unsuspected critical function for XBP1 in mammalian host defenses.

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          Author and article information

          Journal
          Nat Immunol
          Nature immunology
          Springer Science and Business Media LLC
          1529-2916
          1529-2908
          May 2010
          : 11
          : 5
          Affiliations
          [1 ] Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts, USA.
          Article
          ni.1857 NIHMS290444
          10.1038/ni.1857
          3113706
          20351694
          5d9c3b1f-72e6-4593-bea5-6b65aa83268a

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