JONISOIVA SÄTEILY ja VAPAITTEN RADIKAALIEN MUODOSTUS
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OTSIKKO:
Reaktiivisten
happilajien (ROS) osallistuminen jonisoivan säteilyn indusoimaan
Tollin reseptorien TLR-2 ja TLR-4 ilmenemän ylössäätymiseen
ihmisen monosyyteissä.
Involvement of reactive oxygen species in ionizing radiation–induced upregulation of cell surface Toll-like receptor 2 and 4 expression in human monocytic cells
Journal of
Radiation Research, Volume 58, Issue 5, 1 September 2017, Pages
626–635, https://doi.org/10.1093/jrr/rrx011
Published:
22 March 2017
Article history
Abstract
Toll-like receptors
(TLRs) are pattern recognition receptors that recognize
pathogen-associated molecular patterns (PAMPs) and are indispensable
for antibacterial and antiviral immunity. Our previous report showed
that ionizing radiation increases the cell surface expressions of
TLR2 and TLR4 and enhances their responses to agonists in human
monocytic THP1 cells.
The present study
investigated how ionizing radiation increases the cell surface
expressions of TLR2 and TLR4 in THP1 cells . The THP1 cells treated
or not treated with pharmaceutical agents such as cycloheximide and
N-acetyl-L-cysteine (NAC) were exposed to X-ray irradiation
(5Gy) , following which the expressions of TLRs and mitogen-activated
protein kinase (MAPK) were analyzed.
X-ray irradiation
increased the mRNA expressions of TLR2 and TLR4, and treatment with a
protein synthesis inhibitor cycloheximide abolished the
radiation-induced upregulation of their cell surface expressions.
These results
indicate that radiation increased those receptors through de
novo protein synthesis. Furthermore, treatment with
an antioxidant NAC suppressed not only the radiation-induced
upregulation of cell surface expressions of TLR2 and TLR4, but also
the radiation-induced activation of the c-Jun N-terminal kinase
(JNK) pathway.
Since it has been
shown that the inhibitor for JNK can suppress the radiation-induced
upregulation of TLR expression, the present results suggest that
ionizing radiation increased the cell surface expressions of TLR2 and
TLR4 through reactive oxygen species (ROS) –mediated JNK
activation.
Issue Section:
INTRODUCTION
Toll-like receptors
(TLRs) are pattern recognition receptors that recognize
pathogen-associated molecular patterns (PAMPs). TLRs are
indispensable for antibacterial and antiviral immunity [1, 2].
TLRs
are receptive to various components of bacterial cell walls. For
example, TLR2 and TLR4 recognize peptidoglycan (PG)
from gram-positive bacteria and lipopolysaccharide (LPS) from
gram-negative bacteria, subsequently initiating host defense
responses against bacteria.
In contrast, TLR3 and TLR9 recognize
genes of single-strand RNA (ssRNA) viruses as well as DNA viruses
such as herpes simplex virus (HSV) , and initiate the production of
antiviral cytokines such as type I interferon (IFN-I)
Many reports have
shown the link between TLRs and radiation response,
e.g. the radioprotective and/or radiomitigative effects of TLR
agonists [3–7].
Burdelya et
al. reported that injection of CBLB502 (a TLR5
agonist), before lethal total-body irradiation, can improve
the survival of irradiated rhesus monkeys as well as mice [3].
Furthermore, it has
been reported that TLR2–/– mice are more susceptible to ionizing
radiation–induced mortality because of severe bone marrow cell
loss, and wild-type (wt) mice pre-treated with TLR2 agonist show
resistance to ionizing-induced motility [6].
In addition to the
exogenous danger molecules PAMPs, TLRs recognize endogenous
danger molecules, the so-called damage-associated molecular
patterns (DAMPs) [8, 9]. It has been shown that the responses of
TLRs to DAMPs such as host RNA and high-mobility group box 1 (HMGB1),
which are released from damaged cells, also cause biological
responses, including the radiation response [8–12].
Takemura et
al. reported the involvement of TLR3 in
the pathogenesis of gastrointestinal syndrome induced by ionizing
radiation [11]. They showed that radiation-induced crypt cell
death causes leakage of cellular RNA, which in turn induces
extensive crypt cell death via TLR3, leading to gastrointestinal
syndrome.
Furthermore, Apetoh
et al. reported that
HMGB1 secreted from dying tumor cells as a result of radiotherapy or
chemotherapy activates TLR4 on dendritic cells (DC), which results in
the induction of antitumor effects through processing and
cross-presentation of antigen from dying tumor cells [12].
Collectively, these
reports indicate that TLRs play important roles in radiation
response, including radiation-induced tissue damages and the efficacy
of cancer radiotherapy.
We recently
investigated the effects of ionizing radiation on TLR2 and TLR4 by
using human monocytic THP1 cells and THP1-derived macrophage-like
cells, and we showed that ionizing radiation affects the cell surface
expression levels of those receptors and the response to their
agonist depending on the cell differentiation state [13].
In undifferentiated
THP1 cells, the cell surface expressions of TLR2 and TLR4 were shown
to increase after X-irradiation, which was accompanied by the
enhancement of the proinflammatory response induced by their
agonists.
Therefore, it is
possible that ionizing radiation enhances the inflammatory responses
at least by upregulating the cell surface expressions of TLR2 and
TLR4. However, the mechanism responsible for the increases in the
cell surface expressions of TLR2 and TLR4 due to ionizing radiation
remains unknown. Therefore, in the present study, we investigated the
mechanisms by which ionizing radiation increases the cell surface
expressions of TLR2 and TLR4 in human monocytic THP1 (human ac. monocyte leucemia) cells.
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- ANOTHER INTERESTING ASPECT :The role of CERAMIDES
Involvement of ceramide generation in cell surface TLR2 and TLR4 expressions
Ceramide is an
important molecule as the precursor for all major sphingolipids and
serves as a secondary messenger in several signaling pathways
[19].
It is known that genotoxic stimuli and cellular stress,
including ionizing radiation, increase cellular ceramide,
which then causes various cellular responses such as apoptosis
[19–21].
Recently, oxidative stress was reported to increase cell
surface expression of TLR4 in murine macrophages through ceramide
generation [22].
Therefore, we next
investigated the involvement of ceramide in the radiation-induced
upregulation of cell surface expressions of TLR2 and TLR4 using
certain ceramide generation inhibitors. As shown in Fig. 3A,
fumonisin B1 and GW4869 decreased the cell surface expressions of
TLR2 and/or TLR4, whereas desipramine had no effects on the cell
surface expression of either TLR2 or TLR4.
These results suggest that
certain ceramide generation pathways were involved in the cell
surface expressions of TLR2 and TLR4 of non-irradiated THP1 cells.
However, neither ceramide generation inhibitors decreased the
radiation-induced upregulation of cell surface expressions of TLR2
and TLR4 (Fig. 3B).
Fig. 3.
19
Yang J, Yu Y, Sun S,
et al. . Ceramide and other sphingolipids in cellular
responses. Cell Biochem Biophys 2004;40:323–50.
20
Takahashi E, Inanami
O, AsanumaT, et al. . Effects of ceramide inhibition on
radiation-induced apoptosis in human leukemia MOLT-4 cells. J Radiat
Res 2006;47:19–25.
21
Aureli M, MurdicaV,
LobertoN, et al. . Exploring the link between ceramide and
ionizing radiation. Glycoconj J 2014;31:449–59.
22
Tawadros PS, Powers
KA, Ailenberg M, et al. .
Oxidative stress
increases surface Toll-like receptor 4 expression in murine
macrophages via ceramide generation. Shock
2015;44:157–65.
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