1. Increased sensitivity of Treg cells from patients with PBC to low dose IL-12 drives their differentiation into IFN-γ secreting cells
- Author
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Gwilym J. Webb, Samita R. Patel, Sarah Akiror, Benjamin A Fisher, Simon J. Bowman, Evaggelia Liaskou, Danai Bagkou Dimakou, Dave Jones, Francesca Barone, Mahesh Krishna, Gideon M. Hirschfield, and George F. Mells
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_treatment ,Cholangitis, Sclerosing ,Immunology ,Autoimmunity ,Lymphocyte Activation ,medicine.disease_cause ,Interleukin-23 ,T-Lymphocytes, Regulatory ,Interleukin-12 Subunit p35 ,Monocytes ,Primary sclerosing cholangitis ,Interferon-gamma ,03 medical and health sciences ,IL12A ,Humans ,Immunology and Allergy ,Medicine ,Autoimmune disease ,Liver Cirrhosis, Biliary ,business.industry ,Cell Differentiation ,Middle Aged ,STAT4 Transcription Factor ,Th1 Cells ,medicine.disease ,Interleukin-12 ,digestive system diseases ,In vitro ,Hedgehog signaling pathway ,Phenotype ,Sjogren's Syndrome ,030104 developmental biology ,Cytokine ,Gene Expression Regulation ,Case-Control Studies ,Interleukin 12 ,Th17 Cells ,Female ,business - Abstract
IL-12 is a pro-inflammatory cytokine that induces the production of interferon-γ (IFNγ) and favours the differentiation of T helper 1 (Th1) cells. In the presence of IL-12 human Treg cells acquire a Th1-like phenotype with reduced suppressive activity in vitro. Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease characterised by high Th1 and Th17 infiltrating cells, reduced frequencies of Treg cells, and a genetic association with IL-12 signalling. Herein, we sought to evaluate the IL-12 signalling pathway in PBC pathology, by studying human samples from patients with PBC, alongside those with primary Sjögren's syndrome (pSS)(autoimmune disease with IL-12 signalling gene association), primary sclerosing cholangitis (PSC) (cholestatic liver disease without IL-12 gene association) and healthy individuals. Our data revealed that TLR stimulation of PBC (n = 17) and pSS monocytes (n = 6) resulted in significant induction of IL12A mRNA (p 0.05, p 0.01, respectively) compared to PSC monocytes (n = 13) and at similar levels to HC monocytes (n = 8). PSC monocytes expressed significantly less IL-12p70 (108 pg/ml, mean) and IL-23 (358 pg/ml) compared to HC (458 pg/ml and 951 pg/ml, respectively) (p 0.01, p 0.05). Treg cells from patients with PBC (n = 16) and pSS (n = 3) but not PSC (n = 10) and HC (n = 8) responded to low dose (10 ng/ml) IL-12 stimulation by significant upregulation of IFNγ (mean 277 and 254 pg/ml, respectively) compared to PSC and HC Treg cells (mean 22 and 77 pg/ml, respectively)(p 0.05). This effect was mediated by the rapid and strong phosphorylation of STAT4 on Treg cells from patients with PBC and pSS (p 0.05) but not PSC and HC. In the liver of patients with PBC (n = 7) a significantly higher proportion of IL-12Rβ2
- Published
- 2018
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