Expression of Functional Aromatic Hydrocarbon Receptor and Aromatic Hydrocarbon Nuclear Translocator Proteins in Murine Bone Marrow Stromal Cells

Lavin, Amy L.; Hahn, Denise J.; Gasiewicz, Thomas A.

doi:10.1006/abbi.1998.0587

Cited by 22 publications

(10 citation statements)

References 58 publications

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“…Using two different in vitro bone-forming models it was shown that TCDD inhibits bone formation and that a novel AhR antagonist, resveratrol, partially and in some cases completely reverses this inhibition. The competition studies confirm that these effects are mediated through the AhR as shown in other systems (Birnbaum 1994, Sukhu et al 1997, Lavin et al 1998. Currently no endogenous ligand (4 10 8 M to 1 10 5 M).…”

Section: Discussionsupporting

confidence: 73%

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Singh¹,

Casper²,

Fritz³

et al. 2000

Journal of Endocrinology

129

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Aryl hydrocarbon receptor (AhR) ligands are environmental contaminants found in cigarette smoke and other sources of air pollution. The prototypical compound is TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin), also known as dioxin. There is an increasing body of knowledge linking cigarette smoking to osteoporosis and periodontal disease, but the direct effects of smokeassociated aryl hydrocarbons on bone are not well understood. Through the use of resveratrol (3,5,4 -trihydroxystilbene), a plant antifungal compound that we have recently demonstrated to be a pure AhR antagonist, we have investigated the effects of TCDD on osteogenesis. It was postulated that TCDD would inhibit osteogenesis in bone-forming cultures and that this inhibition would be antagonized by resveratrol. We employed the chicken periosteal osteogenesis (CPO) model, which has been shown to form bone in vitro in a pattern morphologically and biochemically similar to that seen in vivo, as well as a rat stromal cell bone nodule formation model. In the CPO model, alkaline phosphatase (AP) activity was reduced by up to 50% (P<0·01 vs control) in the presence of 10 9 M TCDD and these effects were reversed by 10 6 M resveratrol (P<0·05 vs TCDD alone). TCDD-mediated inhibition of osteogenesis was restricted primarily to the osteoblastic differentiation phase (days 0-2) as later addition did not appear to have any effects. Message levels for important bone-associated proteins (in the CPO model) such as collagen type I, osteopontin, bone sialoprotein and AP were inhibited by TCDD, an effect that was antagonized by resveratrol. Similar findings were obtained using the rat stromal bone cell line. TCDD (at concentrations as low as 10 10 M) caused an approximately 33% reduction in AP activity, which was abrogated by 3·5 10 7 M resveratrol. TCDD also induced a marked reduction in mineralization (75%) which was completely antagonized by resveratrol. These data suggest that AhR ligands inhibit osteogenesis probably through inhibition of osteodifferentiation and that this effect can be antagonized by resveratrol. Since high levels of AhR ligands are found in cigarette smoke, and further since smoking is an important risk factor in both osteoporosis and periodontal disease, it may be postulated that AhR ligands are the component of cigarette smoke linking smoking to osteoporosis and periodontal disease. If so, resveratrol could prove to be a promising preventive or therapeutic agent for smoking-related bone loss.

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Section: Discussionsupporting

confidence: 73%

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Singh¹,

Casper²,

Fritz³

et al. 2000

Journal of Endocrinology

129

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“…11 Expression of ARNT/HIF-1␤ has been noted in murine bone marrow primary stromal cell cultures as well as in stromal cell lines. 12 The ARNT/HIF-1␤ knockout data are consistent with other experiments that implicate a role for the VEGF receptor Flk-1, another potential target gene for HIF-1␣ or EPAS1/HIF-2␣, in the in vitro generation of early hematopoietic cells. 13,14 The ARNT/HIF-1␤ data reveal that HIF complexes may be essential for hematopoietic development.…”

Section: Introductionsupporting

confidence: 88%

The HIF family member EPAS1/HIF-2α is required for normal hematopoiesis in mice

Scortegagna

Morris

Oktay

et al. 2003

Blood

180

154

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“…In contrast, Yamaguchi et al (1997) did not detect the AhR in bone marrow B220 þ B cells or in an early pre-B-cell line, but as in the above study, functional AhR was detected in bone marrow stromal cell lines (Lavin et al, 1998;Yamaguchi et al, 1997) and as mentioned earlier in splenic B cells (Marcus et al, 1998). Taken together, these results support an AhR-dependent effect by TCDD on early progenitor cell function.…”

Section: Effects Of Tcdd On B-cell Maturationmentioning

confidence: 44%

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Sulentic

Kaminski

2010

Toxicological Sciences

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Suppression of humoral immune responses by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was first reported in the mid-1970s. Since this initial observation, much effort has been devoted by many laboratories toward elucidation of the cellular and molecular mechanisms responsible for the profound impairment of humoral immune responses by TCDD, which is characterized by decreased B cell to plasma cell differentiation and suppression of immunoglobulin production. These efforts have led to a significant body of research demonstrating a direct effect of TCDD on B-cell maturation and function as well as a requisite but as yet undefined role of the aryl hydrocarbon receptor (AhR) in these effects. Likewise, a number of molecular targets putatively involved in mediating B-cell dysfunction by TCDD, and other AhR ligands, have been identified. However, our current understanding has primarily relied on findings from mouse models, and the translation of this knowledge to effects on human B cells and humoral immunity in humans is less clear. Therefore, a current challenge is to determine how TCDD and the AhR affect human B cells. Efforts have been made in this direction but continued progress in developing adequate human models is needed. An in-depth discussion of these advances and limitations in elucidating the cellular and molecular mechanisms putatively involved in the suppression of B-cell function by TCDD as well as the implications on human diseases associated in epidemiological studies with exposure to TCDD and dioxin-like compounds is the primary focus of this review.Key Words: 2,3,7,8-tetrachlorodibenzo-p-dioxin; B cell; humoral immunity; immune suppression; AhR.Halogenated aromatic hydrocarbons such as the polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls are persistent environmental toxicants. The most potent of this class of chemicals is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which is produced as a by-product during a variety of industrial and municipal processes, many of which involve the combustion of organic materials in the presence of chlorine. TCDD has generated much public concern due to several highly publicized incidents of human and wildlife exposure (reviewed by White and Birnbaum, 2009). Additionally, the sensitivity of rodent models to TCDD-induced toxicity has fueled concern regarding the potential health risks to humans. TCDD produces a broad range of biological effects in animal and cellular models including death, a generalized wasting syndrome, lymphoid involution (especially of the thymus), hepatotoxicity, cardiotoxicity, teratogenicity, developmental toxicity, carcinogenesis, neurotoxicity, immunotoxicity, and various biochemical effects (reviewed by Birnbaum and Tuomisto, 2000).Alterations in immune function, primarily immune suppression, have been observed in virtually every species studied and occurs at doses that do not produce obvious signs of toxicity in vivo and at noncytotoxic concentrations in vitro (Holsapple et al., 1991b;Kerkvliet, 2002). These alterations include ...

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Expression of Functional Aromatic Hydrocarbon Receptor and Aromatic Hydrocarbon Nuclear Translocator Proteins in Murine Bone Marrow Stromal Cells

Cited by 22 publications

References 58 publications

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

Inhibition of dioxin effects on bone formation in vitro by a newly described aryl hydrocarbon receptor antagonist, resveratrol

The HIF family member EPAS1/HIF-2α is required for normal hematopoiesis in mice

The Long Winding Road toward Understanding the Molecular Mechanisms for B-Cell Suppression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin

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