Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C.

Abstract:

BACKGROUND & AIMS:Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. METHODS:Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. RESULTS:We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. CONCLUSIONS:Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.

journal_name

J Hepatol

journal_title

Journal of hepatology

authors

Langhans B,Krämer B,Louis M,Nischalke HD,Hüneburg R,Staratschek-Jox A,Odenthal M,Manekeller S,Schepke M,Kalff J,Fischer HP,Schultze JL,Spengler U

doi

10.1016/j.jhep.2013.04.011

subject

Has Abstract

pub_date

2013-08-01 00:00:00

pages

229-35

issue

2

eissn

0168-8278

issn

1600-0641

pii

S0168-8278(13)00264-X

journal_volume

59

pub_type

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