Preventive effects of 1,25-(OH)2VD3 against ConA-induced mouse hepatitis through promoting vitamin D receptor gene expression.
OBJECTIVE
To investigate the immunosuppressive effects of 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)VD(3)) on concanavalin A (ConA)-induced hepatitis and elucidate the action mechanism.


METHODS
Female BALB/C mice were intravenously administered ConA (20 mg/kg) to induce acute immunological liver injury. Liver damage was evaluated in respect to serum alanine transaminase (ALT) level and liver histological changes. The proliferation of splenocytes was measured by using [(3)H]-thymidine incorporation. The cytokine level in the cultured splenocyte supernatant was determined by using enzyme-linked immunosorbent assays (ELISAs). The percentage of different splenic T cell subtypes was analyzed by using flow cytometry. The expression of splenic vitamin D receptor (VDR) mRNA and protein was detected by using real-time qRT-PCR and Western blot, respectively.


RESULTS
1,25-(OH)(2)VD(3) (2.5 microg/kg, ip) significantly decreased the serum ALT levels and markedly attenuated the histological liver damage. The beneficial effect of 1,25-(OH)(2)VD(3) was associated with: (i) inhibition of CD4(+) T cell activation; (ii) reduction of interferon-gamma (IFN-gamma) and elevation of both IL-4 and IL-5 in supernatants of cultured splenocytes; and (iii) elimination of activated T cells by increasing VDR mRNA and protein expression in the spleen.


CONCLUSIONS
1,25-(OH)(2)VD(3) had a significant protective effect against ConA-induced hepatitis, and its mechanism of action was associated with down-regulation of T cell-mediated immunity and up-regulation of VDR gene expression.
Key Laboratory of Liver and Kidney Diseases of Education Ministry, Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai Research Institute of Traditional Chinese Medicine, Shanghai, China.
Xu-dong
XD
Hu
Shi-li
SL
Jiang
Cheng-hai
CH
Liu
Yi-yang
YY
Hu
Cheng
C
Liu
Ming-yu
MY
Sun
Gao-feng
GF
Chen
Ping
P
Liu
D000410:Alanine Transaminase / Q000032:analysis; D000818:Animals; D016516:CD4-CD8 Ratio; D002117:Calcitriol / Q000627:therapeutic use*; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000517:prevention & control*; D003208:Concanavalin A; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D019693:Hepatitis, Autoimmune / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000276:immunology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014815:Vitamins / Q000627:therapeutic use*
D016207:Cytokines; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014815:Vitamins; D003208:Concanavalin A; D000410:Alanine Transaminase; D002117:Calcitriol