Over the past decade, PAS domains have been identified in dozens of signal transduction molecules and various forms have been found in animals, plants, and prokaryotes. In this review, we summarize this rapidly expanding research area by providing a detailed description of three signal transduction pathways that utilize PAS protein heterodimers to drive their transcriptional output. It is hoped that these model pathways can provide a framework for use in understanding the biology of the less well-understood members of this emerging superfamily, as well as of those to be characterized in the days to come. We use this review to develop the idea that most eukaryotic PAS proteins can be classified by functional similarities, as well as by predicted phylogenetic relationships. We focus on the a-class proteins, which often act as sensors of environmental signals, and the b-class proteins, which typically act as broad-spectrum partners that target these heterodimers to their genomic targets.

The PAS Superfamily: Sensors of Environmental and Developmental Signals

There is growing evidence that fossil fuel combustion products act as adjuvants in the immune system and may lead to enhancement of allergic inflammation. Through this mechanism, particulate air pollutants may be an important contributor to the increased prevalence and morbidity of asthma and allergic rhinitis. In this communication we focus on the role of diesel exhaust particles (DEPs) in skewing the immune response towards IgE production and induction of allergic inflammation. We review experimental studies in animals and humans showing that DEPs enhance IgE production by a variety of mechanisms, including effects on cytokine and chemokine production, as well as activation of macrophages and other mucosal cell types. We discuss metabolic and cellular activation pathways linked to chemicals such as polycyclic aromatic hydrocarbons contained in DEPs and demonstrate how these molecular events may impact cytokine, chemokine, and accessory molecule expression in the immune system.

Enhancement of allergic inflammation by the interaction between diesel exhaust particles and the immune system

The effects of polycyclic aromatic hydrocarbons on the immune system of fish: a review.

http://web.mit.edu/hyneslab/pdfs/Differential%20Requirements.pdf

Differential Requirements for α4 Integrins during Fetal and Adult Hematopoiesis

The RelA NF-κB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c- myc promoter in mammary cells

In the absence of known endogenous ligands, investigators have exploited ubiquitous environmental pollutants, including polycyclic aromatic hydrocarbons, to gain insight into the physiologic functions of the aryl hydrocarbon (dioxin) receptor/transcription factor (AhR). AhR ligands induce cell transformation and steroid-like immunosuppression, suggesting a role for the AhR in regulation of cell growth and/or function. However, mechanisms through which the AhR influences cells in general and lymphocytes in particular remain unresolved. A murine model of B cell development was created to: 1) examine a role for the AhR in immunosuppression; 2) define mechanisms of AhR ligand immunosuppression; 3) characterize AhR expression in preB cells, in bone marrow stromal cells that support preB cells, or in primary bone marrow B cells; and 4) determine if AhR ligands suppress lymphopoiesis by acting directly on preB cells or indirectly via the microenvironment, as represented by bone marrow stromal cells. Results indicate that: 1) low doses (> or = 10(-8) M) of the prototypic AhR ligand, 7,12-dimethylbenz[a]anthracene (DMBA), induce preB cell apoptosis in 12 to 24 h; 2) alpha-naphthoflavone, an AhR and cytochrome P-450 inhibitor, blocks DMBA-induced apoptosis; 3) AhR mRNA and functional AhR protein are expressed at high levels in bone marrow stromal cells (little or no AhR is present in preB cell lines), and 4) preB cells maintained in rIL-7 do not undergo DMBA-induced apoptosis unless cultured with stromal cells. Results underscore the regulatory role played by bone marrow stromal cells in lymphopoiesis and support the hypothesis that the AhR effects immunosuppression by inducing stromal cells to deliver a death signal to lymphocytes.

Koichi Yamaguchi

Papers

Activation of the aryl hydrocarbon receptor/transcription factor and bone marrow stromal cell-dependent preB cell apoptosis.

Induction of PreB cell apoptosis by 7,12-dimethylbenz[a]anthracene in long-term primary murine bone marrow cultures.

Fluoranthene-Induced Apoptosis in Murine T Cell Hybridomas Is Independent of the Aromatic Hydrocarbon Receptor

The Role of Peritoneal Stromal Cells in the Survival of sIgM+ Peritoneal B Lymphocyte Populations1