Upregulation of interferon-gamma and interleukin-4, Th cell-derived cytokines by So-Shi-Ho-Tang (Sho-Saiko-To) occurs at the level of antigen presenting cells, but not CD4 T cells.
BACKGROUND
So-Shi-Ho-Tang (SSHT) or known as Sho-Saiko-To in Japanese and Xiao-Chai-Hu-Tang in Chinese has been used to treat chronic liver disease and other infections, and its hepatoprotective effects have been widely studied.


OBJECTIVE
We tried to investigate the immunomodulatory effect of SSHT on interferon (IFN)-gamma and interleukin (IL)-4 and their Th1/Th2 transcription factors in vivo and in vitro since these two cytokines are important in determining the type of cell-mediated inflammatory and humoral responses.


METHODS
SSHT was orally given to BALB/c mice for 7 days and then injected with anti-CD3 mAb intravenously. IFN-gamma, IL-4, IL-2 and Th1/Th2-specific transcription factors as well as splenocyte subsets were measured. Splenocytes and CD4 T cells were cultured with anti-CD3 or anti-CD3/anti-CD28 in the presence of SSHT, its constituent herbs and baicalin, and the levels of cytokines and transcription factors were measured by ELISA and western blotting.


RESULTS
Oral administration of SSHT to mice in response to i.v. anti-CD3 injection enhanced the expression of IFN-gamma, IL-4 and IL-2 in the serum and spleen at the secreted protein and mRNA level. This was accompanied by the upregulation of CD69 and CD4 T cell populations by flow cytometry. The upregulation of IFN-gamma and IL-4 by SSHT did not occur in anti-CD3/anti-CD28 stimulated CD4 T cells in vitro. However, SSHT was capable of producing the cytokines in anti-CD3 stimulated splenocytes even in the absence of CD28, suggesting a role for some soluble factors produced by antigen presenting cells (APC). In support of this, we found that SSHT increased IL-12 and IL-6 in the same cells. STAT4, but not T-bet, was involved in the upregulation of IFN-gamma by SSHT while the increased IL-4 expression was accompanied by a parallel increase in c-Maf but independent of STAT6 and GATA-3.


CONCLUSIONS
These data indicate that the upregulation of IFN-gamma and IL-4 by SSHT must occur through some interactions between APC and CD4 T cells. Taken together, the present data provide additional information on some of the immunological mechanisms of SSHT for treatment of liver diseases and infections.
Department of Oriental Medical Science, Graduate School of East-West Medical Science, Kyunghee University, 1 Seochungdong, Yongin, South Korea. shehee@khu.ac.kr
Hee
H
Kang
Tae-Won
TW
Choi
Kyoo-Seok
KS
Ahn
Ju-Young
JY
Lee
In-Hye
IH
Ham
Ho-Young
HY
Choi
Eun-Sheb
ES
Shim
Nak-Won
NW
Sohn
D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism*; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D004365:Drugs, Chinese Herbal; C461320:shosaiko-to; D015847:Interleukin-4; D007371:Interferon-gamma