| pmid | 10954742 | ||||
|---|---|---|---|---|---|
| title | Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor. | ||||
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| journal | Proc Natl Acad Sci U S A | ||||
| year | 2000 | ||||
| full_text_available | true | ||||
| full_text_extraction_method | html | ||||
| pmcid | PMC27764 | ||||
| doi | 10.1073/pnas.170291697 |
Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.
Authors: Dumoutier L, Van Roost E, Colau D, Renauld JC Journal: Proc Natl Acad Sci U S A (2000) DOI: 10.1073/pnas.170291697 PMC: PMC27764
- Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):10144-9. doi: 10.1073/pnas.170291697.
Human interleukin-10-related T cell-derived inducible factor: molecular cloning and functional characterization as an hepatocyte-stimulating factor.
Dumoutier L(1), Van Roost E, Colau D, Renauld JC.
Author information: (1)Ludwig Institute for Cancer Research, Brussels Branch and the Experimental Medicine Unit, Christian de Duve Institute of Cellular Pathology, Université Catholique de Louvain, Avenue Hippocrate 74, B1200-Brussels, Belgium.
IL-10-related T cell-derived inducible factor (IL-TIF or IL-21) is a new cytokine structurally related to IL-10 and originally identified in the mouse as a gene induced by IL-9 in T cells and mast cells. Here, we report the cloning of the human IL-TIF cDNA, which shares 79% amino acid identity with mouse IL-TIF and 25% identity with human IL-10. Recombinant human IL-TIF was found to activate signal transducer and activator of transcription factors-1 and -3 in several hepatoma cell lines. IL-TIF stimulation of HepG2 human hepatoma cells up-regulated the production of acute phase reactants such as serum amyloid A, alpha1-antichymotrypsin, and haptoglobin. Although IL-10 and IL-TIF have distinct activities, antibodies directed against the beta chain of the IL-10 receptor blocked the induction of acute phase reactants by IL-TIF, indicating that this chain is a common component of the IL-10 and IL-TIF receptors. Similar acute phase reactant induction was observed in mouse liver upon IL-TIF injection, and IL-TIF expression was found to be rapidly increased after lipopolysaccharide (LPS) injection, suggesting that this cytokine contributes to the inflammatory response in vivo.
DOI: 10.1073/pnas.170291697 PMCID: PMC27764 PMID: 10954742 [Indexed for MEDLINE]
Abstract
IL-10-related T cell-derived inducible factor (IL-TIF or IL-21) is a new cytokine structurally related to IL-10 and originally identified in the mouse as a gene induced by IL-9 in T cells and mast cells. Here, we report the cloning of the human IL-TIF cDNA, which shares 79% amino acid identity with mouse IL-TIF and 25% identity with human IL-10. Recombinant human IL-TIF was found to activate signal transducer and activator of transcription factors-1 and -3 in several hepatoma cell lines. IL-TIF stimulation of HepG2 human hepatoma cells up-regulated the production of acute phase reactants such as serum amyloid A, α1-antichymotrypsin, and haptoglobin. Although IL-10 and IL-TIF have distinct activities, antibodies directed against the β chain of the IL-10 receptor blocked the induction of acute phase reactants by IL-TIF, indicating that this chain is a common component of the IL-10 and IL-TIF receptors. Similar acute phase reactant induction was observed in mouse liver upon IL-TIF injection, and IL-TIF expression was found to be rapidly increased after lipopolysaccharide (LPS) injection, suggesting that this cytokine contributes to the inflammatory response in vivo .
Discussion
In the present paper, we report the cloning of the human IL-TIF cDNA and show that this new cytokine is able to up-regulate acute phase reactant production by liver cells. Production of acute phase proteins is considered as a survival mechanism for the short term, but its maintenance for longer periods contributes to chronic inflammation and may have negative clinical consequences ( 11 , 12 ). This liver response is mainly due to cytokine release by activated macrophages and other cells, particularly IL-1, tumor necrosis factor, and IL-6 ( 13 – 16 ).
The finding that IL-TIF up-regulates acute phase reactant production extends the number of cytokines that might contribute to this process. In addition, we show that the activity of this factor is mediated by IL-10Rβ. This transmembrane protein is required for IL-10 signaling ( 10 ), and IL-10Rβ-deficient mice recapitulate the phenotype of IL-10-deficient mice, namely a high susceptibility to inflammatory bowel disease and splenomegaly ( 17 ). Our data indicate that this molecule is not only a component of the IL-10 receptor complex but might be shared between a larger family of cytokine receptors for IL-10-related factors. This observation also suggests that further analysis of IL-10Rβ-deficient mice might unmask unique characteristics as compared to IL-10 deficient animals, that could reflect IL-TIF-dependent processes.
In addition, it is likely that other members of the IL-10 family that could also use IL-10Rβ will be described in the near future. Recently, a new cytokine called AK155 was identified because of its up-regulation during viral infection of T lymphocytes ( 6 ). This protein shares 27% amino acid identity with IL-10 and shows a similar homology with IL-TIF. Interestingly, the AK155 gene is located on chromosome 12q15, at 40 kb from the IFNγ gene, whereas the IL-TIF gene is located in the very same region, at 90 kb from the IFNγ gene (L.D., unpublished data). This suggests that chromosome 12q15 bears an IFN/IL-10-related cytokine cluster that might be involved in immune and inflammatory responses. In this regard, it must be stressed that chromosome 12q15 has been linked to inflammatory bowel disease and to asthma ( 18 – 21 ). Further analysis of polymorphisms in the human IL-TIF gene and the production of IL-TIF-deficient or transgenic animals should allow us to determine precisely the role of this new factor in inflammatory processes.
IL-TIF was originally identified as a gene up-regulated by IL-9 in a murine T cell lymphoma. This suggested that IL-TIF might be responsible for some of the in vivo activities of IL-9 such as lymphoma induction, asthma susceptibility, anti-parasite immune response, or B1 lymphocyte expansion ( 22 ). Although IL-9 also up-regulated IL-TIF expression in T helper cell clones and mast cell lines in vitro , we failed to detect any up-regulation of this gene in IL-9 transgenic mice, suggesting that it does not play a major role in the in vivo biological activities of IL-9. However, IL-TIF is produced by normal T cells upon ConA activation in mice, or anti-CD3 stimulation in humans, suggesting a role associated with antigen-specific immune responses. In this report, we show that LPS induces IL-TIF mRNA expression in vivo within 2 h in various organs, pointing to other cell types as potential IL-TIF-producers. This finding contrasts with our initial observation that murine spleen cells stimulated for 24 h with LPS in vitro failed to express IL-TIF ( 1 ). This discrepancy between in vivo and in vitro IL-TIF induction might reflect an indirect mechanism of gene induction. Further studies will be necessary to elucidate the mechanisms regulating the expression of this new cytokine during inflammatory processes and to determine potential applications of IL-TIF, itself or its antagonists, in modulating inflammation in vivo .