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Corticotropin-Releasing Factor and the Urocortins Induce the Expression of TLR4 in Macrophages via Activation of the Transcription Factors PU.1 and AP-1¹

Christos Tsatsanis^2,3,*, Ariadne Androulidaki^2,*, Themis Alissafi^*, Ioannis Charalampopoulos, Erini Dermitzaki^*, Thierry Roger, Achille Gravanis and Andrew N. Margioris^3,*

^* Department of Clinical Chemistry-Biochemistry and Department of Pharmacology, School of Medicine, University of Crete, Crete, Greece and Infectious Diseases Service, Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland

Corticotropin-releasing factor (CRF) augments LPS-induced proinflammatory cytokine production from macrophages. The aim of the present study was to determine the mechanism by which CRF and its related peptides urocortins (UCN) 1 and 2 affect LPS-induced cytokine production. We examined their role on TLR4 expression, the signal-transducing receptor of LPS. For this purpose, the murine macrophage cell line RAW 264.7 and primary murine peritoneal macrophages were used. Exposure of peritoneal macrophages and RAW 264.7 cells to CRF, UCN1, or UCN2 up-regulated TLR4 mRNA and protein levels. To study whether that effect occurred at the transcriptional level, RAW 264.7 cells were transfected with a construct containing the proximal region of the TLR4 promoter linked to the luciferase gene. CRF peptides induced activation of the TLR4 promoter, an effect abolished upon mutation of a proximal PU.1-binding consensus or upon mutation of an AP-1-binding element. Indeed, all three peptides promoted PU.1 binding to the proximal PU.1 site and increased DNA-binding activity to the AP-1 site. The effects of CRF peptides were inhibited by the CRF₂ antagonist anti-sauvagine-30, but not by the CRF₁ antagonist antalarmin, suggesting that CRF peptides mediated the up-regulation of TLR4 via the CRF₂ receptor. Finally, CRF peptides blocked the inhibitory effect of LPS on TLR4 expression. In conclusion, our data suggest that CRF peptides play an important role on macrophage function. They augment the effect of LPS by inducing Tlr4 gene expression, through CRF₂, via activation of the transcription factors PU.1 and AP-1.

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