Role of Peroxisome Proliferator-Activated Receptor Gamma and Its Ligands in the Treatment of Hematological Malignancies

Peroxisome proliferator-activated receptor gamma (PPARγ) is a multifunctional transcription factor with important regulatory roles in inflammation, cellular growth, differentiation, and apoptosis. PPARγ is expressed in a variety of immune cells as well as in numerous leukemias and lymphomas. Here, we review recent studies that provide new insights into the mechanisms by which PPARγ ligands influence hematological malignant cell growth, differentiation, and survival. Understanding the diverse properties of PPARγ ligands is crucial for the development of new therapeutic approaches for hematological malignancies

Electrophilic Peroxisome Proliferator–Activated Receptor-γ Ligands Have Potent Antifibrotic Effects in Human Lung Fibroblasts

Pulmonary fibrosis is a progressive scarring disease with no effective treatment. Transforming growth factor (TGF)-β is up-regulated in fibrotic diseases, where it stimulates differentiation of fibroblasts to myofibroblasts and production of excess extracellular matrix. Peroxisome proliferator–activated receptor (PPAR) γ is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that a novel PPARγ ligand, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), is a potent inhibitor of TGF-β–stimulated differentiation of human lung fibroblasts to myofibroblasts, and suppresses up-regulation of α–smooth muscle actin, fibronectin, collagen, and the novel myofibroblast marker, calponin. The inhibitory concentration causing a 50% decrease in aSMA for CDDO was 20-fold lower than the endogenous PPARγ ligand, 15-deoxy-Δ12,14-prostaglandin J2 (15 d-PGJ2), and 400-fold lower than the synthetic ligand, rosiglitazone. Pharmacologic and genetic approaches were used to demonstrate that CDDO mediates its activity via a PPARγ-independent pathway. CDDO and 15 d-PGJ2 contain an α/β unsaturated ketone, which acts as an electrophilic center that can form covalent bonds with cellular proteins. Prostaglandin A1 and diphenyl diselenide, both strong electrophiles, also inhibit myofibroblast differentiation, but a structural analog of 15 d-PGJ2 lacking the electrophilic center is much less potent. CDDO does not alter TGF-β–induced Smad or AP-1 signaling, but does inhibit acetylation of CREB binding protein/p300, a critical coactivator in the transcriptional regulation of TGF-β–responsive genes. Overall, these data indicate that certain PPARγ ligands, and other small molecules with electrophilic centers, are potent inhibitors of critical TGF-β–mediated profibrogenic activities through pathways independent of PPARγ. As the inhibitory concentration causing a 50% decrease in aSMA for CDDO is 400-fold lower than that in rosiglitazone, the translational potential of CDDO for treatment of fibrotic diseases is high

Ocular Fibroblast Diversity: Implications for Inflammation and Ocular Wound Healing

Fibroblasts mediate immune function and may account for differences in susceptibility of the different ocular tissues to become inflamed. Recognizing these differences will promote the development of novel therapeutic strategies for diseases of the eye

Immune Mechanisms in Thyroid Eye Disease

Thyroid eye disease (TED) is an inflammatory condition of the orbit closely associated with Graves' disease. During the course of TED, fibrosis can develop around the extraocular muscles, and excess extracellular matrix and fat accumulates in the periorbital space. This dramatic remodeling results in protrusion of the eye, also known as exophthalmos. Current treatments are sometimes effective in alleviating the symptoms of the disease, but there remains a demand for treatments that prevent or reverse the pathological alterations of orbital tissues. Such treatments may become available as a result of research aimed at understanding the mechanism by which Graves' disease leads to specific remodeling of orbital tissues. Recent findings have uncovered the importance of intercellular communication between autoreactive T cells and orbital fibroblasts. When orbital fibroblasts are activated, possibly by Graves' disease–related autoantibodies, they release T cell chemoattractants, initiating an interaction in which these cells activate each other. These interactions ultimately result in fibroblasts expressing extracellular matrix molecules, proliferating and differentiating into myofibroblasts or lipofibroblasts. Although the mechanisms underlying these processes are not completely understood, several currently available therapeutic strategies might interrupt the signaling between B and T cells and fibroblasts, thereby treating the clinical manifestations of TED

Novel anti-adipogenic activity produced by human fibroblasts

Fatty tissue is generally found in distinct “depots” distributed throughout the human body. Adipocytes from each of the various depots differ in their metabolic capacities and their responses to environmental stimuli. Although a general understanding of the factors responsible for adipogenic transformation has been achieved, much is not understood about the mechanisms of adipose tissue deposition and the phenotypes of the adipocytes found within each depot. A clue to the factors regulating fat deposition may come from studies of adipogenesis using primary human orbital fibroblasts from patients with thyroid eye disease, a condition in which intense inflammation leads to expansion of orbital adipose tissue via differentiation of fibroblasts to adipocytes. We have previously demonstrated that adipogenesis of orbital fibroblasts is negatively correlated with cellular expression of the Thy-1 surface marker. In this study, we developed a novel imaging flow cytometric approach for the assessment of adipogenesis to test the hypothetical dependence of adipogenic potential on lack of Thy-1 expression. Using this technique, we learned that Thy-1-positive fibroblasts are, in fact, capable of differentiating into adipocytes but are less likely to do so because they secrete a paracrine anti-adipogenic factor. It is possible that such a factor plays an important role in the prevention of excess fat deposition in the normal orbit and may even be exploited as a therapy for the treatment of obesity, a major worldwide health concern

Consensus on the Key Characteristics of Immunotoxic Agents as a Basis for Hazard Identification

BackgroundKey characteristics (KCs), properties of agents or exposures that confer potential hazard, have been developed for carcinogens and other toxicant classes. KCs have been used in the systematic assessment of hazards and to identify assay and data gaps that limit screening and risk assessment. Many of the mechanisms through which pharmaceuticals and occupational or environmental agents modulate immune function are well recognized. Thus KCs could be identified for immunoactive substances and applied to improve hazard assessment of immunodulatory agents.ObjectivesThe goal was to generate a consensus-based synthesis of scientific evidence describing the KCs of agents known to cause immunotoxicity and potential applications, such as assays to measure the KCs.MethodsA committee of 18 experts with diverse specialties identified 10 KCs of immunotoxic agents, namely, 1) covalently binds to proteins to form novel antigens, 2) affects antigen processing and presentation, 3) alters immune cell signaling, 4) alters immune cell proliferation, 5) modifies cellular differentiation, 6) alters immune cell-cell communication, 7) alters effector function of specific cell types, 8) alters immune cell trafficking, 9) alters cell death processes, and 10) breaks down immune tolerance. The group considered how these KCs could influence immune processes and contribute to hypersensitivity, inappropriate enhancement, immunosuppression, or autoimmunity.DiscussionKCs can be used to improve efforts to identify agents that cause immunotoxicity via one or more mechanisms, to develop better testing and biomarker approaches to evaluate immunotoxicity, and to enable a more comprehensive and mechanistic understanding of adverse effects of exposures on the immune system. https://doi.org/10.1289/EHP10800