Identification and functional characterization of a second chain of the interleukin-10 receptor complex

Kotenko, Serguei V.; Krause, Christopher D.; Izotova, Lara S.; Pollack, Brian P.; Wu, Wei; Pestka, Sidney

doi:10.1093/emboj/16.19.5894

Cited by 354 publications

(302 citation statements)

References 75 publications

(203 reference statements)

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“…This receptor pair is not used by any other known ligand, although the CRF2-4 chain is also part of the IL-10, IL-22 and IL-26 receptors. [4][5][6][7] Binding of the IFN-l ligand to its receptor initiates signaling reminiscent of the Type-I interferons. In particular, STAT2 is phosphorylated, ISGF3 is activated and OAS and MxA are induced.…”

Section: Introductionmentioning

confidence: 99%

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

et al. 2007

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Interferon lambda-1 (IFN-l1/IL-29) is a member of the Type-III interferon family, which contains three ligands: IFN-l1, 2 and 3. These three ligands use the same unique heterodimeric receptor composed of CRF2-12 (IFN-l-R1/IL-28Ra) and CRF2-4 (IL10-R-b) chains. Like their close relatives, the Type-I interferons, IFN-l1, 2 and 3, promote the phosphorylation of STAT1 and STAT2, induce the ISRE3 complex, elevate OAS and MxA expression and exhibit antiviral activity in vitro. Their use of the IL10-R-b chain and their ability to phosphorylate STAT3, STAT4 and STAT5 suggested that they may also exhibit immunomodulatory activity; their antiviral action led us to hypothesize that this activity might be directed toward the Th1/Th2 system. Here, we have demonstrated that IFN-l1 altered the activity of Th cells in three separate experimental systems: (i) mitogen stimulation, (ii) mixed-lymphocyte reaction (MLR) and (iii) stimulation of naive T cells by monocyte-derived dendritic cells (mDC). In Con-A stimulation assays, the inclusion of IFN-l1 consistently led to markedly diminished levels of secreted interleukin (IL-13) with occasional coincident, modest elevation of secreted IFN-g. IL-13 secretion was 100-fold more sensitive to IFN-l1 than was IFN-g secretion. These observations were also made in the allogeneic two-way MLR. IFN-l1 was able to alter cytokine-mediated Th biasing and when naive T cells were exposed to allogeneic mDC that had been matured in the presence of IFN-l1, secreted IL-13 was again markedly and consistently reduced, whereas secreted IFN-g was largely unaltered. These functions were independent of IL-10. Our data support a hitherto unsuspected role for IFN-l1 in modulating the development of Th1 and Th2 cells, with an apparent emphasis on the diminution of IL-13 secretion.

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Section: Introductionmentioning

confidence: 99%

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

et al. 2007

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“…19,[27][28][29] The IL-10R1 chain plays a dominant role in mediating high-affinity ligandbinding and signal transduction, whereas the IL-10R2 subunit is thought to be required for signaling. 30,31 Interaction of IL-10 with the IL-10R complex stabilizes dimerization of both IL-10R subunits, activates phosphorylation of the receptor-associated Janus tyrosine kinases, Jak1 and Tyk2 32,33 and induces mainly STAT3-mediated signal transduction. [34][35][36] Our group recently identified two novel SNP of the IL-10R1, 37 one of which (G330R, SNP4) affects IL-10-mediated inhibition of TNFa production in human monocytes.…”

Section: Introductionmentioning

confidence: 99%

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

et al. 2005

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Immune response to viral infection is an important determinant of liver injury in chronic hepatitis C (CHC). Experimental and clinical data suggest a protective role of interleukin-10 (IL-10) in hepatic fibrogenesis. The significance of two SNPs of the interleukin-10 receptor 1 (IL-10R1), S138G (SNP3) and G330R (SNP4) was investigated on (i) susceptibility to CHC, (ii) progression of hepatic fibrosis and (iii) response to interferon/ribavirin therapy. DNA and liver biopsies were obtained from 212 patients with HCV (hepatitis C virus)-genotype-1 infection. The allele frequencies were 0.17 for SNP3 and 0.33 for SNP4, both of which were indifferent from healthy controls (0.17 and 0.32, respectively). Stage 1 liver fibrosis was found in 22 cases (10.4%), stage 2 in 108 (50.9%), stage 3 in 27 (12.8%), and stage 4 (cirrhosis) in 55 (25.9%). An association was found between the SNP4 allele and the presence of cirrhosis (P ¼ 0.01). Homozygous SNP4 individual variants segregated within the cirrhosis group (P ¼ 0.03). We found neither an association with SNP3 nor with the necroinflammatory disease activity (as measured by ALT levels) nor with the response to antiviral therapy. Our work implies that IL-10R1 SNP4 is a recessively inherited risk factor for hepatic cirrhosis in HCV genotype-1 infection.

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“…Cot/tpl2 achieves this control via its kinase activity, because cells expressing Cot/tpl2 KD, or WT macrophages in the presence of PD 0325901, also exhibit impaired TLR activation of Akt and p70 S6k. Furthermore, this novel attribute of Cot/tpl2 in the activation of Akt and p70 S6k is a selective and specific event, since Cot/tpl2 has no effect on the Ser473 Akt phosphorylation or on Thr389 p70 S6k phosphorylation in IL-10-stimulated BMDMs, which utilize a receptor that activates distinct intracellular pathways that the TLR/IL1 receptor super-family [41]. The PI3K-Akt-mTOR-p70 S6k pathway has an established role in restricting pro-inflammatory and promoting anti-inflammatory responses in TLR-stimulated macrophages [7,8,42].…”

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Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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LPS stimulation activates IKK and different MAP kinase pathways, as well as the PI3K-AktmTOR-p70 S6k pathway, a negative regulator of these MyD88-dependent intracellular signals. Here, we show that Cot/tpl2, a MAP3K responsible for the activation of the MKK1-Erk1/2, controls P-Ser473 Akt and P-Thr389 p70 S6k phosphorylation in LPS-stimulated macrophages. Analysis of the intracellular signalling in Cot/tpl2 KO macrophages versus WT macrophages reveals lower IjBa recovery and higher phosphorylation of JNK and p38a after 1 h of LPS stimulation. Moreover, Cot/tpl2 deficiency increases LPS-induced NO synthase 2 (NOS2) expression in macrophages. Inhibition of the PI3K pathway abolishes the differences in IjBa and NOS2 expression between Cot/tpl2 KO and WT macrophages following LPS administration. Furthermore, in zymosan-and polyI:C-stimulated macrophages, Cot/tpl2 mediates P-Ser473 Akt phosphorylation, increases IjBa levels and decreases NOS2 expression. In conclusion, these data reveal a novel role for the Cot/tpl2 pathway in mediating TLR activation of the Akt-mTOR-p70 S6k pathway, allowing Cot/tpl2 to fine-control the activation state of other signalling pathways.Key words: Akt . Cot/tpl2 . Macrophage . NO synthase 2 . p70 S6k . TLR See accompanying Commentary by Martinez Supporting Information available online IntroductionStimulation of TLRs by the different PAMPs triggers macrophage activation, starting a specific functional program that culminates in the production of inflammatory mediators. With the exception of TLR3, TLRs use MyD88 as a central intracellular adaptor, thereby activating multiple downstream intracellular pathways including IKK. TLR3 and TLR4 recruit the TRIF adaptor, which also activates IKK, but specifically activating TBK1 and the transcription factor IRF3 (reviewed in [1,2]). Translocation of IRF3 to the nucleus is necessary, although not sufficient, to induce IFN-b expression [3]. Most TLRs also activate the PI3K-Akt-mTOR-p70 S6k pathway, which is considered to be a negative regulator of TLR activation in macrophages and myeloid dendritic cells. Inhibition of this PI3K-Akt-mTOR-p70 S6k pathway in TLR-activated cells augments NO synthase 2 (NOS2) expression [4][5][6][7][8].Adequate TLR4 stimulation induces the formation of a TLR receptor complex that recruits proteins such as MyD88 and p85 PI3 K [9]. PI3K subsequently activates the Akt-mTOR-p70 S6k pathway. Moreover, TLR-bound MyD88 recruits IRAK4 and IRAK1. The phosphorylation of IRAK1 by IRAK4 facilitates TRAF6 [1,10]). Activated IKK-b phosphorylates p105 NF-kB at multiple residues [11][12][13], which targets the rapid degradation of p105 NF-kB to p50 NF-kB [11][12][13][14]. In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully...

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Identification and functional characterization of a second chain of the interleukin-10 receptor complex

Abstract: Identification and functional characterization of a second chain of the interleukin-10 receptor complex cells, blocking their ability to secrete cytokines such as Serguei V.Kotenko, Christopher D.Krause, interferon-γ (IFN-γ) and IL-2 (Fiorentino et al., 1991;

Cited by 354 publications

References 75 publications

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

Human interferon lambda-1 (IFN-λ1/IL-29) modulates the Th1/Th2 response

Bi-allelic presence of the interleukin-10 receptor 1 G330R allele is associated with cirrhosis in chronic HCV-1 infection

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

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