Endogenous IL-10 maintains immune tolerance but IL-10 gene transfer exacerbates autoimmune cholangitis

Yu Hsin Hsueh, Hung Wen Chen, Bi Jhen Syu, Chia I. Lin, Patrick S Leung, M. Eric Gershwin, Ya Hui Chuang

Research output: Contribution to journalArticle

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Abstract

The immunomodulatory effect of IL-10 as an immunosuppressive and anti-inflammatory cytokine is well known. Taking advantage of our established mouse model of autoimmune cholangitis using 2-octynoic acid conjugated ovalbumin (2-OA-OVA) induction, we compared liver pathology, immune cell populations and antimitochondrial antibodies between IL-10 knockout and wild type mice immunized with 2-OA-OVA. At 10 weeks post immunization, portal inflammation and fibrosis were more severe in 2-OA-OVA immunized IL-10 knockout mice than in wild type mice. This was accompanied by significant higher levels of collagen I and III expression, T, NK and NKT subsets in liver and IgG anti-mitochondrial autoantibodies (AMAs) compared to 2-OA-OVA immunized wild type mice, suggesting that endogenous IL-10 is necessary for the maintenance of immune tolerance in primary biliary cholangitis (PBC). Further, we investigated whether administration of exogenous IL-10 could prevent PBC by administration of IL-10 expressing recombinant adeno-associated virus (AAV-IL-10) either 3 days before or 3 weeks after the establishment of liver pathology. Interestingly, administration of AAV-IL-10 resulted in increased liver inflammation and fibrosis, accompanied by increases in IFN-γ in liver CD4+ T cell, granzyme B, FasL, and CD107a in liver CD8+ T and NKT cells, and granzyme B and FasL in liver NK cells of AAV-IL-10 administered mice compared with control mice. Furthermore, administration of AAV-IL-10 significantly increased levels of proinflammatory cytokines and chemokines (IFN-γ, TNF-α, CXCL9 and CXCL10) and collagen I and III production in naïve mice, together with increase in immune cell infiltration and collagen deposition in the liver, suggesting a role of IL-10 in fibrosis. In conclusion, our data demonstrate that endogenous IL-10 is critical in the maintenance of immune tolerance but exogenous administration of IL-10 exacerbates liver inflammation and fibrosis. Furthermore, the distinctive presence of inflammatory immune cell populations and collagen expression in AAV-IL-10 treated naïve mice cautions against the clinical use of exogenous IL-10 in patients with autoimmune cholangitis.

Original languageEnglish (US)
Pages (from-to)159-170
Number of pages12
JournalJournal of Autoimmunity
Volume95
DOIs
StatePublished - Dec 1 2018

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Immune Tolerance
Cholangitis
Interleukin-10
Genes
Ovalbumin
Liver
Collagen
Granzymes
Inflammation
Knockout Mice
Liver Cirrhosis
Fibrosis
Maintenance
Pathology
Cytokines
T-Lymphocytes
Dependovirus
Natural Killer T-Cells
Immunosuppressive Agents
Chemokines

Keywords

  • Adeno-associated virus
  • IFN-γ
  • IL-10
  • Inflammation
  • Liver autoimmune disease

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Endogenous IL-10 maintains immune tolerance but IL-10 gene transfer exacerbates autoimmune cholangitis. / Hsueh, Yu Hsin; Chen, Hung Wen; Syu, Bi Jhen; Lin, Chia I.; Leung, Patrick S; Gershwin, M. Eric; Chuang, Ya Hui.

In: Journal of Autoimmunity, Vol. 95, 01.12.2018, p. 159-170.

Research output: Contribution to journalArticle

Hsueh, Yu Hsin ; Chen, Hung Wen ; Syu, Bi Jhen ; Lin, Chia I. ; Leung, Patrick S ; Gershwin, M. Eric ; Chuang, Ya Hui. / Endogenous IL-10 maintains immune tolerance but IL-10 gene transfer exacerbates autoimmune cholangitis. In: Journal of Autoimmunity. 2018 ; Vol. 95. pp. 159-170.
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AU - Leung, Patrick S

AU - Gershwin, M. Eric

AU - Chuang, Ya Hui

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