1. Introduction
Allergic diseases such as allergic rhinitis, asthma, food allergy,
atopic dermatitis, allergic contact dermatitis, and anaphylaxis
contribute to the rising cost of health care and cause a lower quality
of life. Allergy is characterized by immune responses by
antigen-specific type 2 helper T (Th2) cells that are involved in the
development of antigen-specific immunoglobulin E (IgE) responses
produced following class switching of B cells1. T cell
receptors (TCRs) in naïve CD4+ T cells recognize
antigens upon co-stimulation by CD28 when contacting antigen-presenting
cells (APCs). Antigen presentation to naïve CD4+ T
cells induces their differentiation into effector and memory T cells,
and triggers clonal expansion. Activated T cells produce IL-2, which
stimulates T cell proliferation, by autocrine or paracrine
signaling2,3. Naïve CD4+ T cells can
differentiate into at least four subtypes including Th1, Th2, Th17, and
induced regulatory T (iTreg) cells4. Among these
subsets of CD4+ T cells, Th2 cells are characterized
by their production of interleukin (IL)-4, IL-5, and IL-13, and
stimulate B cell class switching to produce antigen-specific
IgE5.
Heme oxygenases (HO) are essential enzymes that catabolize heme into
iron (Fe), biliverdin, and carbon monoxide (CO). Three isoforms of HO
exist: the inducible form (HO-1) and constitutive forms (HO-2 and HO-3).
In particular, HO-1 is an inducible enzyme expressed in mammalian
tissues and plays a cytoprotective role6–8. It is
well established that oxidative stress activates the nuclear factor
erythroid 2-related factor 2 (NRF2) pathway resulting in HO-1
expression. In turn, HO-1 plays an essential role in maintaining
intracellular homeostasis against excess reactive oxygen species (ROS)
generated by redox signaling9, and protects cells
against oxidative stress and inflammation10,11. In
addition, HO-1 can regulate cell proliferation by arresting the
cell-cycle by generating CO12,13. Previous studies
investigating regulatory effects of HO-1 on T cells revealed that CO
generated by HO-1 also suppresses CD4+ T cell
proliferation by inhibiting IL-2 production14, and CO
exposure suppresses proliferation and activation of T
cells15,16. Phytochemicals obtained through fruit and
vegetable consumption have protective effects against diverse diseases
by inducing HO-1 expression by activating the NRF2
pathway17. Among these phytochemicals, quercetin, the
aglycone of miqeulianin, has been reported to protect cells from
oxidative stress and inflammation by generating
HO-118,19, and recently, it was reported that
quercetin suppresses T cell proliferation via HO-1
generation20.
In a previous study, we revealed
that Rosae multiflorae fructus extract ameliorates OVA-induced
allergic rhinitis symptoms in a mouse model, and identified miquelianin
as the active compound of Rosae multifloraefructus21. Miqeulianin (quercetin
3-O -glucuronide, MQL), one of the flavonoids, is a quercetin
glycoside. MQL has been reported to have
antioxidant22, antidepressant23, and
antiproliferative effects24. However, it is unknown if
MQL affects allergic diseases or regulates Th2 immune responses. Thus,
in this study, we examined the effect of MQL on a TMA-induced AD-like
mouse model, and investigated the mechanisms by which MQL regulates
Th2-related immune responses in vitro .