The aryl hydrocarbon receptor (dioxin/PCBs), herpesvirus infections and underactive macrophages
Kofi
macrophages. There are a variety of reasons for this. Aside from the
genetic ones or autoantibodies, macrophage dysfunction could be caused
by viral infection or toxic exposure - and we're starting to see why
these things occur hand-in-hand. To sum up my findings, the Aryl
hydrocarbon receptor (ahR) accepts toxins like PCB and dioxins as
ligands. Activated, ahR signaling then degrades vitamin D3 faster -
perhaps accounting for the association of PCBs with infection and
cancer. The herpes family, as I have noted before, can upregulate the
ahR [PMID 16257957] making the host more sensitive to the presence of
these toxins. I believe this helps explain the overlap with CMV/EBV
infections and autoimmune diseases like Crohn�s since
1) the viruses upregulate the ahR and this degrades vit D
2) separate studies show the viruses depress macrophages which are
already depressed in Crohn�s
and
3) the ahR regulates macrophage inflammation/activation.
It looks like these three are all related.
1: Comput Biol Chem. 2009 Oct 23
�
Promoters of the genes encoding the transcription factors regulating the
cytokine gene expression in macrophages contain putative binding sites
for aryl hydrocarbon receptor.
Furman DP, Oshchepkova EA, Oshchepkov DY, Shamanina MY, Mordvinov VA.
Institute of Cytology and Genetics, Siberian Branch, Russian Academy of
Sciences, pr. Lavrentieva 10, Novosibirsk 630090, Russia; Novosibirsk
State University, ul. Pirogova 2, Novosibirsk 630090, Russia.
The computer system SITECON was used to study the regulatory regions in
the transcription factor genes expressed in the activated macrophage and
the genes of the proteins mediating the macrophage involvement in the
immune response. Dioxin responsive elements (DREs), the specific sites
responsible for expression regulation of the genes involved in the cell
response to dioxin, were found in these gene regions. Thus, the role of
dioxin in activity regulation of the genes involved in development of
the immune response can be regulated both directly, by the transcription
complex containing dioxin as a ligand, and indirectly, via intrinsic
transcription factors.The double regulation, via DRE and the binding
sites for the corresponding transcription factors in the promoter
regions of macrophage genes, and the interregulation of the genes
providing for the immune response allow the system to rapidly respond to
a provocative agent (xenobiotic) and finely tune its function.
PMID: 19906563
Mol Cell Biol. 2009 Oct 12
Hypersensitivity of AhR-deficient mice to LPS-induced septic shock.
Sekine H, Mimura J, Oshima M, Okawa H, Kanno J, Igarashi K, Gonzalez FJ,
Ikuta T, Kawajiri K, Fujii-Kuriyama Y.
The Center for Tsukuba Advanced Research Alliance and Institute of Basic
Medical Sciences, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba
305-8577, Japan; Division of Molecular Toxicology, National Institute of
Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan;
Laboratory of Metabolism, Center for Cancer Research, National Cancer
Institute, National Institutes of Health, Bethesda, MD 20892, USA;
Research Institute for Clinical Oncology, Saitama Cancer Center, 818
Komuro, Ina-machi, Kitaadachi-gun,Saitama 362-0806, Japan; SORST, Japan
Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, 332-0012, Japan.
Aryl hydrocarbon receptor (AhR), a ligand-activated transcription
factor, is known to mediate a wide variety of pharmacological and
toxicological effects caused by polycyclic aromatic hydrocarbons. Recent
studies have revealed that AhR is involved in the normal development and
homeostasis of many organs. Here, we demonstrate that AhR KO mice are
hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly
due to the dysfunction of their macrophages. In response to LPS, AhR KO
bone marrow-derived macrophages (BMDM) secreted an enhanced amount of
IL-1beta. Since the enhanced IL-1beta secretion was suppressed by
supplementing Plasminogen activator inhibitor-2 (Pai-2) expression
through transduction with Pai-2-expressing adenoviruses, reduced Pai-2
expression could be a cause of the increased IL-1beta secretion by AhR
KO BMDM. Analysis of gene expression revealed that AhR directly
regulates the expression of Pai-2 through a mechanism involving
NF-kappaB, but not AhR nuclear translocator (Arnt) in a LPS-dependent
manner. Together with the result that administration of the AhR ligand,
3-methylcholanthrene (3MC) partially protected AhR WT mice from
endotoxin-induced death, these results raise the possibility that an
appropriate AhR ligand may be useful for treating patients with
inflammatory disorders.
PMID: 19822660
Oral Microbiol Immunol. 2009 Jun;24(3):243-8
�
Human cytomegalovirus and Epstein-Barr virus inhibit oral
bacteria-induced macrophage activation and phagocytosis.
Lin YL, Li M.
Department of Oral Health Research, University of Kentucky College of
Dentistry, Lexington, KY, USA.
INTRODUCTION: Periodontal disease is an inflammatory condition caused by
periodontal microorganisms. Viruses such as human cytomegalovirus (HCMV)
and Epstein-Barr virus (EBV) are associated with certain types of
periodontal disease, but their roles in promoting the disease are
unclear. Because both viruses infect human macrophages, cells which play
key roles in the clearance of pathogenic bacteria, it is likely that the
viruses alter the functional capacity of macrophages by inhibiting their
defense mechanisms against invading pathogens. METHODS: Macrophages
preinfected with HCMV or EBV were evaluated following stimulation by
selected oral bacteria. Bacteria-induced macrophage activation was
assayed by measuring the levels of tumor necrosis factor-alpha
(TNF-alpha) produced in the media, and phagocytic activity was analysed
by a phagocytosis assay with fluorescein isothiocyanate-labeled
bacteria. The virus-infected macrophages were also subjected to
semi-quantitative polymerase chain reaction to measure the expression of
toll-like receptor 9, which is involved in the activation of
phagocytosis-related pathways. RESULTS: Both HCMV and EBV significantly
diminished the TNF-alpha production typically induced by oral bacteria,
inhibited the phagocytic activity of macrophages, and downregulated the
expression of toll-like receptor 9. CONCLUSION: Infection by HCMV or EBV
inhibits the functional ability of macrophages to respond to bacterial
challenge, thereby suggesting their pathogenic role in the development
of periodontal disease.
Publication Types:
* Research Support, N.I.H., Extramural
PMID: 19416455