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Type I IFN induced IL1-Ra expression in hepatocytes is mediated by activating STAT6 through the formation of STAT2: STAT6 heterodimer.

Wan L, Lin CW, Lin YJ, Sheu JJ, Chen BH, Liao CC, Tsai Y, Lin WY, Lai CH, Tsai FJ - J. Cell. Mol. Med. (2008)

Bottom Line: The biological activities of type I interferons (IFNs) are mediated by their binding to a heterodimer receptor complex (IFNAR1 and IFNAR2), resulting in the activation of the JAK (JAK1 and TYK2)-STAT (1, 2, 3, 5 isotypes) signalling pathway.In addition, IFN-alpha or IFN-beta significantly enhanced the stimulatory effect of IL-1beta on production of IL-1Ra.Our results provide evidence for the mechanism how IFN-alpha and IFN-beta modulate inflammatory responses through activation of STAT6 and production of secreted IL-1Ra.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, Taiwan. leiwan@www.cmuh.org.tw

ABSTRACT
The biological activities of type I interferons (IFNs) are mediated by their binding to a heterodimer receptor complex (IFNAR1 and IFNAR2), resulting in the activation of the JAK (JAK1 and TYK2)-STAT (1, 2, 3, 5 isotypes) signalling pathway. Although several studies have indicated that IFN-alpha and IFN-beta can activate complexes containing STAT6, the biological role of this activation is still unknown. We found that exposure of hepatoma cells (HuH7 and Hep3B) to IFN-alpha or IFN-beta led to the activation of STAT6. Activated STAT6 in turn induced the formation of STAT2: STAT6 complexes, which led to the secretion of IL-1Ra. The activation of STAT6 by type I IFN in hepatocytes was mediated by JAK1 and Tyk2. In addition, IFN-alpha or IFN-beta significantly enhanced the stimulatory effect of IL-1beta on production of IL-1Ra. The present study suggests a novel function of IFN-alpha and IFN-beta signalling in human hepatocytes. Our results provide evidence for the mechanism how IFN-alpha and IFN-beta modulate inflammatory responses through activation of STAT6 and production of secreted IL-1Ra.

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A model for STAT6 activation on IFNα/β signalling. Tyk2 is pre-associated with IFNAR1, while JAK1, STAT2 are pre-associated with IFNAR2c. IFNα and IFNβ induce the receptor hetero-dimerization and subsequently the IFNAR1 is phosphorylated and binds to STAT2, which is then phosphorylated at Tyr690. The phospho-STAT2 binds to IFNAR2 and recruited STAT1 or STAT6 to the receptor. Subsequently, STAT1 or STAT6 is then phospho-rylated at Tyr701 or Tyr641, respectively, by JAK1 or Tyk2. The phosophorylated STAT6 will form a homodimer and bind to the IL-Ra promoter, thereby inducing the transcription of IL-Ra.
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fig06: A model for STAT6 activation on IFNα/β signalling. Tyk2 is pre-associated with IFNAR1, while JAK1, STAT2 are pre-associated with IFNAR2c. IFNα and IFNβ induce the receptor hetero-dimerization and subsequently the IFNAR1 is phosphorylated and binds to STAT2, which is then phosphorylated at Tyr690. The phospho-STAT2 binds to IFNAR2 and recruited STAT1 or STAT6 to the receptor. Subsequently, STAT1 or STAT6 is then phospho-rylated at Tyr701 or Tyr641, respectively, by JAK1 or Tyk2. The phosophorylated STAT6 will form a homodimer and bind to the IL-Ra promoter, thereby inducing the transcription of IL-Ra.

Mentions: The IFN-α or IFN-β activation pathway, in which ligands trigger the activation of STATs, begins by inducing dimerization of IFNAR1 and IFNAR2, which leads to the activation of JAK1 and Tyk2 kinases. It has been demonstrated that the phosphorylation of STAT2 at Tyr 690 is required for efficient activation of STAT1 [39–41]. In U6A cells, a mutant cell line which lacks STAT2, the phosphorylation of STAT1 is weak. We have also demonstrated that the down-regulation of STAT2 by RNAi reduced the phosphorylation of STAT1 (data not shown) [40]. The stimulation of HuH7 cells with IFN- or IFN- results in the association between STAT2/STAT6. Moreover, the activation of STAT6 and the expression of IL-1Ra were inhibited by inhibiting STAT2 protein expression (Fig. 2C and 5B). These observations prompt us to suggest a mechanism through which STAT6 is activated by IFN-α or IFN-β (Fig. 6). According to this mechanism, binding of IFN-α or IFN-β to their high-affinity receptors leads to the dimerization of IFNAR1 and IFNAR2. The activated JAK1 and Tyk2 kinases then activate STAT2 by phosphorylating Tyr 690. The phosphorylated-STAT2 seems to provide a docking site for STAT1 [39] and STAT6, where they are subsequently activated following phosohprylation at Tyr 701 and 641, respectively. Phosphorylated-STAT6 then dissociates from the docking site, homodimer-izes, and binds to the promoter of the IL-Ra gene, thereby initiating transcription of IL-Ra mRNA. Such activation mechanism may also occur with the formation of the STAT1: STAT1 homodimer, which is known to be activated by IFNγ. Indeed, IFNα has been shown to contribute to efficient IFN signalling through the homodimerization of STAT1. However, whether the STAT2: STAT6 heterodimer binds to DNA and activates gene expression remains unknown.


Type I IFN induced IL1-Ra expression in hepatocytes is mediated by activating STAT6 through the formation of STAT2: STAT6 heterodimer.

Wan L, Lin CW, Lin YJ, Sheu JJ, Chen BH, Liao CC, Tsai Y, Lin WY, Lai CH, Tsai FJ - J. Cell. Mol. Med. (2008)

A model for STAT6 activation on IFNα/β signalling. Tyk2 is pre-associated with IFNAR1, while JAK1, STAT2 are pre-associated with IFNAR2c. IFNα and IFNβ induce the receptor hetero-dimerization and subsequently the IFNAR1 is phosphorylated and binds to STAT2, which is then phosphorylated at Tyr690. The phospho-STAT2 binds to IFNAR2 and recruited STAT1 or STAT6 to the receptor. Subsequently, STAT1 or STAT6 is then phospho-rylated at Tyr701 or Tyr641, respectively, by JAK1 or Tyk2. The phosophorylated STAT6 will form a homodimer and bind to the IL-Ra promoter, thereby inducing the transcription of IL-Ra.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401122&req=5

fig06: A model for STAT6 activation on IFNα/β signalling. Tyk2 is pre-associated with IFNAR1, while JAK1, STAT2 are pre-associated with IFNAR2c. IFNα and IFNβ induce the receptor hetero-dimerization and subsequently the IFNAR1 is phosphorylated and binds to STAT2, which is then phosphorylated at Tyr690. The phospho-STAT2 binds to IFNAR2 and recruited STAT1 or STAT6 to the receptor. Subsequently, STAT1 or STAT6 is then phospho-rylated at Tyr701 or Tyr641, respectively, by JAK1 or Tyk2. The phosophorylated STAT6 will form a homodimer and bind to the IL-Ra promoter, thereby inducing the transcription of IL-Ra.
Mentions: The IFN-α or IFN-β activation pathway, in which ligands trigger the activation of STATs, begins by inducing dimerization of IFNAR1 and IFNAR2, which leads to the activation of JAK1 and Tyk2 kinases. It has been demonstrated that the phosphorylation of STAT2 at Tyr 690 is required for efficient activation of STAT1 [39–41]. In U6A cells, a mutant cell line which lacks STAT2, the phosphorylation of STAT1 is weak. We have also demonstrated that the down-regulation of STAT2 by RNAi reduced the phosphorylation of STAT1 (data not shown) [40]. The stimulation of HuH7 cells with IFN- or IFN- results in the association between STAT2/STAT6. Moreover, the activation of STAT6 and the expression of IL-1Ra were inhibited by inhibiting STAT2 protein expression (Fig. 2C and 5B). These observations prompt us to suggest a mechanism through which STAT6 is activated by IFN-α or IFN-β (Fig. 6). According to this mechanism, binding of IFN-α or IFN-β to their high-affinity receptors leads to the dimerization of IFNAR1 and IFNAR2. The activated JAK1 and Tyk2 kinases then activate STAT2 by phosphorylating Tyr 690. The phosphorylated-STAT2 seems to provide a docking site for STAT1 [39] and STAT6, where they are subsequently activated following phosohprylation at Tyr 701 and 641, respectively. Phosphorylated-STAT6 then dissociates from the docking site, homodimer-izes, and binds to the promoter of the IL-Ra gene, thereby initiating transcription of IL-Ra mRNA. Such activation mechanism may also occur with the formation of the STAT1: STAT1 homodimer, which is known to be activated by IFNγ. Indeed, IFNα has been shown to contribute to efficient IFN signalling through the homodimerization of STAT1. However, whether the STAT2: STAT6 heterodimer binds to DNA and activates gene expression remains unknown.

Bottom Line: The biological activities of type I interferons (IFNs) are mediated by their binding to a heterodimer receptor complex (IFNAR1 and IFNAR2), resulting in the activation of the JAK (JAK1 and TYK2)-STAT (1, 2, 3, 5 isotypes) signalling pathway.In addition, IFN-alpha or IFN-beta significantly enhanced the stimulatory effect of IL-1beta on production of IL-1Ra.Our results provide evidence for the mechanism how IFN-alpha and IFN-beta modulate inflammatory responses through activation of STAT6 and production of secreted IL-1Ra.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Genetics and Medical Research, China Medical University Hospital, Taichung, Taiwan. leiwan@www.cmuh.org.tw

ABSTRACT
The biological activities of type I interferons (IFNs) are mediated by their binding to a heterodimer receptor complex (IFNAR1 and IFNAR2), resulting in the activation of the JAK (JAK1 and TYK2)-STAT (1, 2, 3, 5 isotypes) signalling pathway. Although several studies have indicated that IFN-alpha and IFN-beta can activate complexes containing STAT6, the biological role of this activation is still unknown. We found that exposure of hepatoma cells (HuH7 and Hep3B) to IFN-alpha or IFN-beta led to the activation of STAT6. Activated STAT6 in turn induced the formation of STAT2: STAT6 complexes, which led to the secretion of IL-1Ra. The activation of STAT6 by type I IFN in hepatocytes was mediated by JAK1 and Tyk2. In addition, IFN-alpha or IFN-beta significantly enhanced the stimulatory effect of IL-1beta on production of IL-1Ra. The present study suggests a novel function of IFN-alpha and IFN-beta signalling in human hepatocytes. Our results provide evidence for the mechanism how IFN-alpha and IFN-beta modulate inflammatory responses through activation of STAT6 and production of secreted IL-1Ra.

Show MeSH
Related in: MedlinePlus