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NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides.

ABSTRACT: Interferons are cytokines that play a complex role in the resistance of mammalian hosts to pathogens. IFNgamma (interferon-gamma) is secreted by activated T-cells and natural killer cells. IFNgamma is involved in a wide range of physiological processes, including antiviral activity, immune response, cell proliferation and apoptosis, as well as the stimulation and repression of a variety of genes. IFNgamma activity is modulated by the binding of its C-terminal domain to HS (heparan sulphate), a glycosaminoglycan found in the extracellular matrix and at the cell surface. In the present study, we analysed the interaction of isolated heparin-derived oligosaccharides with the C-terminal peptide of IFNgamma by NMR, in aqueous solution. We observed marked changes in the chemical shifts of both peptide and oligosaccharide compared with the free state. Our results provide evidence of a binding through electrostatic interactions between the charged side chains of the protein and the sulphate groups of heparin that does not induce specific conformation of the C-terminal part of IFNgamma. Our data also indicate that an oligosaccharide size of at least eight residues displays the most efficient binding.

SUBMITTER: Vanhaverbeke C

PROVIDER: S-EPMC1134092 | biostudies-literature | 2004 Nov

REPOSITORIES: biostudies-literature

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NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides.

Vanhaverbeke Cécile C Simorre Jean-Pierre JP Sadir Rabia R Gans Pierre P Lortat-Jacob Hugues H

The Biochemical journal 20041101 Pt 1

Interferons are cytokines that play a complex role in the resistance of mammalian hosts to pathogens. IFNgamma (interferon-gamma) is secreted by activated T-cells and natural killer cells. IFNgamma is involved in a wide range of physiological processes, including antiviral activity, immune response, cell proliferation and apoptosis, as well as the stimulation and repression of a variety of genes. IFNgamma activity is modulated by the binding of its C-terminal domain to HS (heparan sulphate), a g ...[more]

PMID: 15270718

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Project description:ImportanceLaryngotracheal stenosis (LTS) is a fibroproliferative disorder of the glottis, subglottis, and trachea. In models of fibrosis from other organ systems, the CD4+ T-cell response has been shown to regulate extracellular matrix deposition. Specifically, helper T cell 2 (TH2) promotes fibrosis, whereas TH1 and associated cytokines have been shown to be antifibrotic. However, this antifibrotic effect of the TH1 response has not been demonstrated in LTS.ObjectiveTo determine whether the TH1 cytokine interferon-γ inhibits the function of LTS-derived fibroblasts in vitro.Design, setting, and participantsThis in vitro controlled study included 6 patients with iatrogenic LTS undergoing routine surgical subglottic and tracheal dilation at a single institution. Fibroblasts were isolated from biopsy specimens of laryngotracheal scar and normal-appearing trachea. The presence of fibroblasts was confirmed by an immunohistochemical analysis. Laryngotracheal stenosis-derived fibroblasts were treated with interferon-γ and compared with untreated controls (2 sets of untreated, LTS-derived fibroblasts [media did not contain interferon-γ]) and normal airway fibroblasts (fibroblasts isolated from normal trachea). Data were collected from August 2015 through June 2016.InterventionsTreatment with interferon-γ, 10 ng/mL.Main outcomes and measuresCellular proliferation, fibrosis gene expression (using quantitative reverse transcription polymerase chain reaction analysis), soluble collagen, and cellular histologic features were assessed.ResultsAmong the 6 patients (6 women; mean [SD] age, 38.3 [17.2] years), LTS-derived fibroblast proliferation was reduced in patients who received interferon-γ treatment compared with untreated controls on days 3 (mean difference, -6515 cells; 95% CI, -10 630 to -2600 cells) to 6 (mean difference, -47 521 cells; 95% CI, -81 285 to -13 757 cells). Interferon-γ treatment reduced collagen types I and III gene expression by 86% and 68%, respectively, and resulted in lower total collagen production (10.94 vs 14.89 μg/mL). In addition, interferon-γ treatment resulted in a 32% reduction in expression of transforming growth factor β in LTS-derived fibroblasts.Conclusions and relevanceInterferon-γ reduced proliferation, soluble collagen production, and collagen expression in LTS-derived fibroblasts while also reducing the expression of the profibrotic cytokine transforming growth factor β. These findings suggest that therapeutics aimed at increasing interferon-γ and the TH1 response could attenuate LTS.

Dataset Information

NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides.

Publications

NMR characterization of the interaction between the C-terminal domain of interferon-gamma and heparin-derived oligosaccharides.

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