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s 458C
Adefovir or Tenofovir Reciprocally Augments
Pro-Inflammatory Cytokines in LPS-Stimulated
PBMC By Inhibiting IL-10 Production in
CD14+monocytes
Kazumoto Murata, Gastroenterology, International University
of Health and Welfare; Genome Medical Sciences Project,
National Center for Global Health and Medicine, Masaya
Sugiyama, Genome Medical Science Project, National Center
for Global Health and Medicine and Masashi Mizokami,
National Center for Global Health and Medicine
Background: Nucleos(t)ide analogues (NUC) can control
hepatitis B virus (HBV) by inhibiting its reverse transcriptase,
but life-long therapies are generally required. We recently
discovered that adefovir (ADV) or tenofovir (TDF) has
an additional pharmacological anti-HBV effect to induce
IFN-l3 in the gastrointestinal (GI) tracts. Since enteric
lipopolysaccharide (LPS) can cross the intestine and spread
into portal vein, we hypothesized that orally administered
NUC could influence LPS-induced cytokine production in
peripheral blood mononuclear cells (PBMC). Methods:
Whole PBMC or various cells (CD3, CD14, CD19, or CD56)-
depleted PBMC obtained from healthy volunteers (HV) were
incubated with NUC (lamivudine; LAM, ADV, entecavir; ETV,
TDF) or negative control (DMSO), following stimulation with
LPS, with or without IFN-a. PBMC from patients with chronic
HBV infection (asymptomatic carriers (AC); n=8, chronic
hepatitis (CH); n=10, liver cirrhosis (LC); n=5) were also used.
Each cytokine level in the supernatant was measured by Bio-
Plex cytokine assay or enzyme-linked immunosorbent assay
(ELISA). In some experiments, antibodies or recombinant
proteins of interleukin (IL)-10, IL-12p70, or tumor necrosis
factor (TNF)-α were used when PBMC were stimulated
with NUC. Results: Bio-Plex cytokine assay revealed that
ADV or TDF significantly induced IL-12p70 and TNF-α,
and inhibited IL-10, compared with DMSO, LAM, and ETV.
These patterns were similarly observed in PBMC from all 3
HV, which were confirmed by ELISA using PBMC from other
HV. No other cytokines were shown to be significant. ADV or
TDF modulated those cytokine levels in a dose-dependent
manner, which was completely abrogated by depletion of
CD14+monocytes. Comparable results were obtained using
PBMC from HBV patients although all cytokine levels were
significantly lower in patients with LC, compared with HV, AC
or CH. Monoclonal antibody and recombinant protein of IL-
10 significantly enhanced and inhibited IL-12p70 or TNF-α,
respectively, in a dose-dependent manner. In contrast, none
of monoclonal antibodies or recombinant proteins of IL-
12p70 and TNF-α changed IL-10 levels regardless of their
concentration used. Collectively, ADV or TDF initially inhibits
LPS-mediated IL-10 production and reciprocally induced IL-
12p70 and TNF-α. In addition, the levels of IL-12p70 were
increased by 4-6 times when combined with IFN-α, whereas
no changes in IL-10 levels were observed. Conclusion: It is
well known that IL-10 is an anti-inflammatory cytokine and IL-
12p70 is a cytokine to enhance cytopathic and non-cytopathic
effects on immune cells. Therefore, our results strongly
suggest that immunological favorable effects on HBV-infected
hepatocytes are theoretically expected by monotherapy
of nucleotide analogues (ADV or TDF) or combination with
IFN-α. The mechanisms of nucleotide analogues on inhibitory
effect of IL-10 production are under investigation. |
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发表于 2018-10-23 15:28