IL-30 (IL27p28) attenuates liver fibrosis through inducing NKG2D-rae1 interaction
between NKT and activated hepatic stellate cells in mice
#MMPMID25351459
Mitra A
; Satelli A
; Yan J
; Xueqing X
; Gagea M
; Hunter CA
; Mishra L
; Li S
Hepatology
2014[Dec]; 60
(6
): 2027-39
PMID25351459
show ga
Chronic hepatic diseases, such as cirrhosis, hepatocellular carcinoma, and
virus-mediated immunopathogenic infections, affect billions of people worldwide.
These diseases commonly initiate with fibrosis. Owing to the various side effects
of antifibrotic therapy and the difficulty of diagnosing asymptomatic patients,
suitable medication remains a major concern. To overcome this drawback, the use
of cytokine-based sustained therapy might be a suitable alternative with minimal
side effects. Here, we studied the therapeutic efficacy and potential mechanisms
of interleukin (IL)-30 as antifibrosis therapy in murine liver fibrosis models.
CCl4 or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) 0.1% (wt/wt) Purina 5015
Chow (LabDiet, St. Louis, MO) was fed for 3 weeks to induce liver fibrosis.
Either control vector (pCtr) or pIL30 was injected hydrodynamically once per
week. A significant decrease in collagen deposition and reduced expression of
alpha-smooth muscle actin (?-SMA) protein indicated that IL-30-based gene therapy
dramatically reduced bridging fibrosis that was induced by CCl4 or DDC.
Immunophenotyping and knockout studies showed that IL-30 recruits
natural-killer-like T (NKT) cells to the liver to remove activated hepatic
stellate cells (HSCs) significantly and ameliorate liver fibrosis. Both flow
cytometric and antibody-mediated neutralization studies showed that liver NKT
cells up-regulate the natural killer group 2, member D (NKG2D) ligand and bind
with the NKG2D ligand, retinoic acid early inducible 1 (Rae1), and positively
activated HSCs to ameliorate liver fibrosis. Furthermore, adoptive transfer of
liver NKT cells in T-cell-deficient mice showed reduction of fibrosis upon IL-30
administration. CONCLUSIONS: Highly target-specific liver NKT cells selectively
remove activated HSCs through an NKG2D-Rae1 interaction to ameliorate liver
fibrosis after IL-30 treatment.
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