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Dynamics of Transforming Growth Factor (TGF)-β Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines.

ABSTRACT: Human immunodeficiency virus type 1 (HIV-1) infection triggers rapid induction of multiple innate cytokines including type I interferons, which play important roles in viral control and disease pathogenesis. The transforming growth factor (TGF)-β superfamily is a pleiotropic innate cytokine family, some members of which (activins and bone morphogenetic proteins (BMPs)) were recently demonstrated to exert antiviral activity against Zika and hepatitis B and C viruses but are poorly studied in HIV-1 infection. Here, we show that TGF-β₁ is systemically induced with very rapid kinetics (as early as 1-4 days after viremic spread begins) in acute HIV-1 infection, likely due to release from platelets, and remains upregulated throughout infection. Contrastingly, no substantial systemic upregulation of activins A and B or BMP-2 was observed during acute infection, although plasma activin levels trended to be elevated during chronic infection. HIV-1 triggered production of type I interferons but not TGF-β superfamily cytokines from plasmacytoid dendritic cells (DCs) in vitro, putatively explaining their differing in vivo induction; whilst lipopolysaccharide (but not HIV-1) elicited activin A production from myeloid DCs. These findings underscore the need for better definition of the protective and pathogenic capacity of TGF-β superfamily cytokines, to enable appropriate modulation for therapeutic purposes.

SUBMITTER: Dickinson M

PROVIDER: S-EPMC7732468 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Dynamics of Transforming Growth Factor (TGF)-β Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines.

Dickinson Matthew M Kliszczak Anna E AE Giannoulatou Eleni E Peppa Dimitra D Pellegrino Pierre P Williams Ian I Drakesmith Hal H Borrow Persephone P

Frontiers in immunology 20201124

Human immunodeficiency virus type 1 (HIV-1) infection triggers rapid induction of multiple innate cytokines including type I interferons, which play important roles in viral control and disease pathogenesis. The transforming growth factor (TGF)-β superfamily is a pleiotropic innate cytokine family, some members of which (activins and bone morphogenetic proteins (BMPs)) were recently demonstrated to exert antiviral activity against Zika and hepatitis B and C viruses but are poorly studied in HIV- ...[more]

PMID: 33329587

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Project description:Growth differentiating factor (GDF)15 is a TGFβ superfamily cytokine and a reported biomarker of heart failure. Myocardial expression of GDF15 is increased in heart failure. Yet, the mechanisms that control synthesis and release of GDF15 as well as the autocrine/paracrine functions of GDF15 on fibroblast function is lacking. Thus, the aim of this study was to investigate signaling pathways and functions of GDF15 in cardiac fibroblasts. Cardiac fibroblasts and cardiac myocytes were isolated from adult C57/BL6 mice, maintained in primary culture and stimulated with recombinant (r)GDF15 or recombinant (r)CCN2. Short-term stimulation (30 minutes) of cardiac fibroblasts demonstrated a GDF15-induced activation of several intracellular signaling pathways including a concentration-dependent increase of phospho-Smad3(Ser423/425) (p<0.05, n=3), phospho-AKT(Ser473) (p<0.05, n=3) and phospho-IκBα(Ser32/36) (p<0.05, n=3) levels. However, rGDF15 did not phosphorylate Smad3(Ser423/425) or IκBα(Ser32/36) in cardiac myocyte. Cardiac fibroblasts exposed to rGDF15 for 48 hours displayed differentiation towards myofibroblasts reflected by increased levels of the differentiation marker α-smooth muscle actin (SMA) similar to cardiac fibroblasts stimulated with TGFβ. The effect of GDF15 on α-SMA was dose-dependent ranging from 500 nM - 20 nM rGDF15 (p<0.05, n=3). Differentiation towards a myofibroblast phenotype in the presence of GDF15 was also supported by higher matrix metalloproteinase (MMP) enzyme activity in the cell culture medium (6±1 fold increase, n=3, p<0.05) and increased expression and release of MMP-3, 9 and 13. Immunoreactive GDF15 was predominantly found in cardiac myocytes. Recombinant CCN2 substantially induced GDF15 expression in cardiac myocytes, but not in cardiac fibroblasts. In conclusion, our data demonstrate that GDF15 is a paracrine factor in myocardial tissue and specifically regulated by CCN2 in cardiac myocytes. GDF15 has similar effects as TGFβ on fibroblasts by activation of intracellular signaling pathways and differentiation to a myofibroblasts phenotype.

Dataset Information

Dynamics of Transforming Growth Factor (TGF)-β Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines.

Publications

Dynamics of Transforming Growth Factor (TGF)-β Superfamily Cytokine Induction During HIV-1 Infection Are Distinct From Other Innate Cytokines.

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