Potential Therapeutic Use of PPAR γ

Dendritic cells (DCs) can regulate all elements of the immune system, and therefore are an ideal target for vaccination. During the last two decades, as a result of extensive research, DCs became the primary target of antitumor vaccination as well. A critical issue of antitumor vaccination is the phenotype of the dendritic cell used. It has been recently shown that several nuclear hormone receptors, and amongst them the lipid-activated nuclear receptor and peroxisome proliferator-activated receptor gamma (PPARγ), have important roles in effecting the immunophenotype of human dendritic cells. It regulates primarily lipid metabolism and via this it influences the immunophenotype of DCs by altering lipid antigen uptake, presentation, and also other immune functions. In this review, we summarize the principles of antitumor vaccination strategies and present our hypothesis on how PPARγ-regulated processes might be involved and could be exploited in the design of vaccination strategies

Nicotinic acid suppresses sebaceous lipogenesis of human sebocytes via activating hydroxycarboxylic acid receptor 2 (HCA )

Nicotinic acid (NA) activates hydroxycarboxylic acid receptor 2 (HCA2), and it is widely used in treating dyslipidemias. Since its side effects include skin dryness, whereas its deficiency can be accompanied by dyssebacia, characterized by sebaceous gland enlargement, we asked if HCA2 is expressed on human sebocytes, and if NA influences sebocyte functions. By using human immortalized SZ95 sebocytes, we found that non-cytotoxic (≤100 μM; MTT-assay) concentrations of NA had no effect on the homeostatic sebaceous lipogenesis (SLG; Nile Red), but normalized excessive, acne-mimicking SLG induced by several lipogenic agents (arachidonic acid, anandamide, linoleic acid+testosterone; Nile Red; 48-hr treatments). Moreover, it exerted significant anti-proliferative actions (CyQUANT-assay), and increased [Ca2+]IC (Fluo-4 AM-based Ca2+-measurement). Although NA did not prevent the lipopolysaccharide-induced pro-inflammatory response (up-regulation [Q-PCR] and release [ELISA] of several pro-inflammatory cytokines) of the sebocytes, collectively, these data support the concept that NA may be effective in suppressing sebum production in vivo. While exploring the mechanism of the sebostatic actions, we found that sebocytes express HCA2 (Q-PCR, immunofluorescent labeling), siRNA-mediated silencing of which prevented the NA-induced Ca2+-signal and the lipostatic action. Collectively, our data introduce NA, and HCA2 activators in general, as novel, potent, and most likely safe sebostatic agents, with possible anti-acne potential.K

A sejtmagi hormon receptorok és a lipid antigének bemutatásának kapcsolata dendritikus sejtekben

A dendritikus sejtek funkcióit befolyásoló molekuláris mechanizmusokat az elmúlt évtizedekben számos kutatócsoport vizsgálta. Munkacsoportunk a dendritikus sejtekben jelenlévő magreceptor család tagjainak szerepét vizsgálja a sejtek funkciójára. A receptor család tagjai lipid érzékelőként működnek. Szerepük a sejt környezetéből érkező, illetve a sejten belül termelődött/aktiválódott lipidek hatásának közvetítése a génkifejeződésre. A lipidek által aktivált magreceptorok olyan koordinált génkifejeződési mintázat változást eredményeznek, melyek megváltozott funkcióval rendelkező dendritikus sejtek kialakuláshoz vezethetnek. Munkánk során a magreceptor család két tagjának, a PPARγ és RARα receptorok szerepét vizsgáltuk a humán monocita eredetű dendritikus sejtek érése során. A PPARγ aktivációja fokozza a retinolt oxidáló enzimek (RDH10 és RALDH) kifejeződését a sejtekben, ami a RARα-t aktiváló csupa transz retinsav (all-trans retinoic acid (ATRA)) termelődéséhez vezet. A receptor továbbá fokozza az ATRA sejtmagba szállításáért felelős (CRABP2) fehérje szintjét. Az ATRA a sejtmagban fizikailag kötődik és aktiválja a RARα receptort, ami beindítja a lipid antigén bemutató CD1d molekula génjének átíródását. A CD1d molekula segítségével a dendritikus sejt az αGC lipid antigént az arra specifikus iNKT sejtek száméra mutatja be. A két magreceptor a lipid antigén bemutatás további lépéseit is szabályozza. Azonosítottuk a katepszin D (CatD) proteázt, mint új PPARγ célgént, összekötve a lizoszómális proteázt molekuláris és funkcionális szinten a DC-alapú lipid prezentáción keresztül történő iNKT sejtfunkciók szabályozásához.The functional flexibility of DCs is frequently accompanied by transcription factor-mediated transcription. DCs express nuclear hormone receptors that translate intra/extracellular signals to the level of gene expression, required for appropriate immune phenotype of the cells. The precise transcription network, which regulates DC immune specificities has to be characterized. Therefore we analyzed the functions of PPARγ and RARα in DCs. PPARγ activation turns on the endogenous ATRA production in DC by up-regulated retinol/retinal oxidizing enzyme genes, namely RDH10 and RALDH2. ATRA is transported to nucleus by the PPARγ-induced CRABP2 transporters, activates RARα, leading to co-ordinated transcriptional regulation of genes, required for lipid antigen presentation, such as CD1d antigen presenting molecules. Lipid antigen-loaded DCs activate CD1d-restricted iNKT cells. We provided evidence that other step of the lipid presentation could be under the control of the two receptors. We identified CatD as a novel target of the PPARγ and linked this lysosomal protease at molecular- and functional level to DC-based lipid presentation to harness iNKT functions.d

VATS therapy of chylothorax caused by leiomyomatosis complicated with tuberous sclerosis complex

Lymphangioleiomyomatosis with tuberous sclerosis complex is a rare disease. One of the most frequent complications of lymphangioleiomyomatosis is pleural effusion (chylothorax) wich can be treated with the use of VATS. Authors report a case of pulmonary lymphangioleiomyomatosis in a 56-year-old female patient with tuberous sclerosis complex with an 8-week history of recurrent chylothorax, dyspnea and debilitating weakness. By CT scan a flat tissue proliferation was seen in the site of the thoracic duct and it was supposed to be the reason for the pleural effusion. A VATS resection of this laesion and ligation of the thoracic duct was performed successfully. Chylothorax is often associated with pulmonary lymphangioleiomyomatosis. Lymphangioleiomyomatosis combined with tuberous sclerosis complex is extremely rare. In case of chylothorax VATS treatment is successful and may be the first choice