Immunopharmacology and Inflammation
Cryptomerione induces Th1 cell polarization via influencing IL-10 production by
cholera toxin-primed dendritic cells
Masao Takei
a,
⁎
, Akemi Umeyama
b
, Je-Jung Lee
a
, Noboru Shoji
b
, Toshihiro Hashimoto
b
a
Research Center for cancer immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeonnam, South Korea
b
Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
abstractarticle info
Article history:
Received 1 April 2009
Received in revised form 4 November 2009
Accepted 16 November 2009
Available online 24 November 2009
Keywords:
Dendritic cells
Cryptomerione
Cholera toxin
Th1 response
Dendritic cells play an important role in the initiation and regulation of immune response. Dendritic cells
have a key influence in the differentiation of naïve T cells into Th1, Th2 or Th17 effector cells. Cryptomerione
is terpene isolated from the heartwood of Cryptomeria japonica. In this study, we investigated the effects of
Cryptomerione on the phenotypic and functional maturation of human monocyte-derived dendritic cells in
vitro. Human monocytes were exposed to either Cryptomerione alone, or in combination with
lipopolysaccaride (LPS) or cholera toxin (CT) and thereafter co-cultured with naïve T cells. We found no
enhanced CD1a, CD80, CD83, CD86 and HLA-DR expression on Cryptomerione-primed dendritic cells.
However, Cryptomerione augmented T cell stimulatory capacity in an allogeneic mixed lymphocyte reaction
to CT-primed dendritic cells and influenced the production of interleukin (IL)-10 and IL-12p70 by CT-primed
dendritic cells, but not LPS-primed dendritic cells. Cryptomerione also inhibited Th2 cell polarization induced
by CT-primed dendritic cells, but enhanced IFN-γ secretion by naïve T cells co-cultured with CT-primed
dendritic cells. Cytokine production by CT-primed dendritic cells alone, or in combination with
Cryptomerione was also influenced following treatment with anti-IL-10 mAb and anti-OX40L mAb. Thus,
the potential mechanisms underlying the enhancement of Th1 polarization in CT-primed dendritic cells
induced by Cryptomerione appeared to depend on IL-10 secretion and OX40L. These results suggest that
Cryptomerione modulates human dendritic cells function in a fashion that favors Th1/Th2 cell polarization.
© 2009 Elsevier B.V. All rights reserved.
1. Introduction
Terpenes contain pharmacologically active substance. We have
recently reported that numerous terpenes induce dendritic cells from
human monocytes and drive Th1, Th2 or IL-10-producing Treg
polarization (Takei et al., 2005, 2006, 2008). It has also been reported
that novel terpenes suppress tumor growth in vivo by inducing anti-
proliferation and pro-apoptosis events (Liu et al., 2008). Cryptomerione
is phytochemically classified as a terpene, and is isolated from the black
heartwood of Cryptomeria japonica. C. japonica D. Don (Tacodiacease),
often called sugi, is a widely distributed conifer in Japan. The wood
collected from C. japonica represents the most popular building material
used in the construction of Japanese housing. Cryptomerione exhibits
numerous interesting biological activities including cytotoxic activity
(Gutierrez and Herz, 1988).
The human immune system is often confronted with antigens and
proteins that have not been previously encountered by the body.
Dendritic cells are professional antigen-presenting cells, are the most
powerful stimulators of naïve T cells and play a key role in the
induction of these immune responses. Upon encountering inflamma-
tory stimuli or pathogens in peripheral tissues, dendritic cells become
activated and undergo a number of physiological changes that lead to
their terminal differentiation or maturation. These changes are linked
to an enhanced ability to activate T cells and to regulate the
differentiation of CD4+ T cells into Th1, Th2 or Th17 type (Romsgnsni,
1994; Steinman, 2007; Martinez et al., 2008). It has been reported that
increased secretion of IL-12 by dendritic cells generates a Th1
response through IFN-γ induction in T cells, and that secretion of IL-
10 by activated dendritic cells results in the generation of Th2 cells or
the T-regulatory type of T cell response (Banchereau and Steinman,
1998). Thus, dendritic cells play a pivotal role in orchestrating the
immune responses. Dendritic cells have also been shown to prime
naïve T cells used as a cellular platform for vaccination in several
encouraging anti-cancer clinical trials that have resulted in an
enhanced tumor antigen-specific immune responses (Banchereau
and Palucka, 2005). Although various terpenes have pharmacological
activity, relatively little is known in regards to the influences
Cryptomerione exerts on the initiation of specific immune responses
at the level of dendritic cells. Therefore, to further understand the
cellular basis of immunological abnormalities associated with Cryp-
tomerione exposure, we examined the effect of Cryptomerione on
human monocyte-derived dendritic cells functions.
European Journal of Pharmacology 628 (2010) 233–239
⁎ Corresponding author. Tel.: +82 61 379 7631; fax: +82 61 379 7628.
E-mail address: mtakei@pep.ne.jp (M. Takei).
0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ejphar.2009.11.031
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