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Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus

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Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus GASTROENTEROLOGY 2010;139:1008–1018 Lysophosphatidic Acid Is a Potential Mediator of Cholestatic Pruritus ANDREAS E. KREMER,* JOB J. W. W. MARTENS,* WIM KULIK,‡ FRANZISKA RUËFF,§ EDITH M. M. KUIPER,ʈ HENK R. VAN BUUREN,ʈ KAREL J. VAN ERPECUM,¶ JURATE KONDRACKIENE,# JESUS PRIETO,** CHRISTIAN RUST,‡‡ VICTORIA L. GEENES,§§ CATHERINE WILLIAMSON,§§ WOUTER H. MOOLENAAR,ʈʈ ULRICH BEUERS,* and RONALD P. J. OUDE ELFERINK* *Tytgat Institute for Liver and Intestinal Research and ‡Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; §Departments of Dermatology and Allergology, University of Munich, Munich, Germany; ‡‡Internal Medicine II - Grosshadern, University of Munich, Munich, Germany; ʈDepartment of Gastroenterology & Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands; ¶Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, The Netherlands; #Department of Gastroenterology, Kaunas University of Medicine, Kaunas, Lithuania; **Department of Medicine and Liver Unit, Clinica Universitaria, Medical School and Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain; §§Maternal and Fetal Disease Group, Institute of Reproductive and Developmental Biology, Imperial College London, London, England; and ʈʈDivision of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands BACKGROUND & AIMS: Pruritus is a common and hronic pruritus is a disabling symptom accompany- disabling symptom in cholestatic disorders. However, its Cing a broad range of systemic disorders such as causes remain unknown. We hypothesized that potential chronic liver diseases, chronic renal failure, malignancies, pruritogens accumulate in the circulation of cholestatic infections, and endocrine and hematologic diseases.1,2 patients and activate sensory neurons. METHODS: Cy- Despite the recent discovery of itch-specific neuronal 2ϩ tosolic free calcium ([Ca ]i) was measured in neuronal pathways, including novel itch mediators and their re- cell lines by ratiometric fluorometry upon exposure to ceptors,1,3,4 the pathogenesis of pruritus remains enig- serum samples from pruritic patients with intrahepatic matic. Regardless of the underlying cause, various chole- cholestasis of pregnancy (ICP), primary biliary cirrhosis static disorders such as intrahepatic cholestasis of (PBC), other cholestatic disorders, and pregnant, healthy, pregnancy (ICP), benign recurrent intrahepatic cholesta- 2ϩ and nonpruritic disease controls. Putative [Ca ]i-induc- sis, progressive familial intrahepatic cholestasis, primary ing factors in pruritic serum were explored by analytical biliary cirrhosis (PBC), and primary sclerosing cholangitis techniques, including quantification by high-perfor- often induce pruritus. These cholestatic liver disorders mance liquid chromatography/mass spectroscopy. In are all characterized by an impairment of hepatocellular mice, scratch activity after intradermal pruritogen injec- and/or cholangiocellular secretory function and bile tion was quantified using a magnetic device. RESULTS: flow.5 In these patients, pruritus may become refractory 2ϩ PANCREAS, AND Transient increases in neuronal [Ca ]i induced by pru- to all medical treatments and can in severe cases be an BILIARY TRACT BASIC–LIVER, ritic PBC and ICP sera were higher than corresponding indication for liver transplantation, even in the absence controls. Lysophosphatidic acid (LPA) could be identified of liver failure.6 In the past, enhanced serum levels of 2ϩ as a major [Ca ]i agonist in pruritic sera, and LPA both bile salts and ␮-opioids have been implicated in the concentrations were increased in cholestatic patients etiology of cholestatic pruritus.7 However, neither corre- with pruritus. LPA injected intradermally into mice in- lations between itch intensity and bile salt or opioid duced scratch responses. Autotaxin, the serum enzyme levels nor a causative link have ever been established. converting lysophosphatidylcholine into LPA, was mark- Autotaxin (ATX) was originally identified in the con- edly increased in patients with ICP versus pregnant con- ditioned medium of human A2058 melanoma cells and Ͻ trols (P .0001) and cholestatic patients with versus described as an autocrine cell motility factor.8 ATX is Ͻ without pruritus (P .0001). Autotaxin activity corre- overexpressed in several other tumor entities and has Ͻ lated with intensity of pruritus (P .0001), which was been linked to tumor cell proliferation, motility, and not the case for serum bile salts, histamine, tryptase, formation of metastasis.9 Physiologically, ATX is re- ␮ substance P, or -opioids. In patients with PBC who quired for angiogenesis and neuronal development, as underwent temporary nasobiliary drainage, both itch in- indicated by ATX-deficient mice, which are embryonic tensity and autotaxin activity markedly decreased during lethal due to vascular malformation and neuronal abnor- drainage and returned to preexistent levels after drain removal. CONCLUSIONS: We suggest that LPA and 2؉ autotaxin play a critical role in cholestatic pruritus Abbreviations used in this paper: ATX, autotaxin; [Ca ]i, cytosolic free calcium; HBSS, Hank’s balanced salt solution; ICP, intrahepatic and may serve as potential targets for future thera- cholestasis of pregnancy; LPA, lysophosphatidic acid; LPC, lysophos- peutic interventions. phatidylcholine; PBC, primary biliary cirrhosis. © 2010 by the AGA Institute Keywords: Autotaxin; Bile Salts; Cholestasis; Itch. 0016-5085/$36.00 doi:10.1053/j.gastro.2010.05.009 September 2010 LPA AND CHOLESTATIC PRURITUS 1009 malities.10,11 Recently, ATX could be identified as an was used to count scratch movements with a low cutoff extracellular secreted enzyme with lysophospholipase D frequency of 10 Hz, a high cutoff frequency of 20 Hz, a activity, which generates lysophosphatidic acid (LPA) threshold level of 300 mV, a minimum of 4 beats per from lysophosphatidylcholine (LPC).12,13 LPA is a small bout, and a maximal coefficient of variation of 40% be- but potent bioactive phospholipid with a wide variety of tween the beats of a bout. The analytical procedure was effects in many cell types ranging from cytoskeletal validated with intradermal compound 48/80, showing a (re)organization and cell migration to cytokine produc- positive predictive value of 95% at a sensitivity of 50%. tion and platelet activation.9,14 Effects of ATX are be- All mouse experiments were approved by the Institu- lieved to be mainly mediated by the enzymatic formation tional Animal Care and Use Committee. of LPA, which activates at least 6 different G protein– coupled receptors.9,15 Most interest in ATX has so far Materials been directed toward its functions in cancer and early Cell culture media were from Lonza (Basel, Swit- development. However, it was recently established that zerland); stearoyl-LPA (LPA 18:1) and myristoyl-LPC LPA plays a crucial role in the induction of neuropathic (LPC 14:0) from Avanti Lipids (Alabaster, AL); choline pain16 and causes reprogramming of gene expression in oxidase, horseradish peroxidase, homovanillic acid, per- different types of afferent nerve fibers.17 tussis toxin, and ionomycin from Sigma-Aldrich (St Here we report that levels of LPA and ATX are mark- Louis, MO); and Ki16245 and ATX antibody for Western edly increased in serum of patients with cholestatic pru- blotting from Cayman (Ann Arbor, MI). Indo-1 AM was ritus. Moreover, serum levels closely correlate with itch from Invitrogen (Carlsbad, CA), and Microcon filters intensity, and intradermal injections of LPA induce were from Millipore (Billerica, MA). scratching behavior in mice. We therefore suggest that LPA and ATX play a critical role in cholestatic itch and Cell Culture may serve as potential targets for future therapeutic in- SH-SY5Y cells were cultured in Ham’s F12K me- terventions. dium containing 10% (vol/vol) fetal bovine serum, peni- cillin (100 IU/mL), streptomycin (100 ␮g/mL), and Materials and Methods L-glutamine (0.2 mmol/L) at 37°C in a humidified atmo- sphere of 5% CO /95% air. Human Subjects 2 Peripheral venous blood was obtained from Fluorometric Measurement of Cytosolic Free healthy donors, pregnant women, and patients with cho- Calcium Levels lestatic disorders after informed consent according to the SH-SY5Y cells were detached, washed twice, and Declaration of Helsinki. The study was approved by the suspended in HEPES-buffered Hank’s balanced salt so- local medical ethical committees. Blood samples were lution (HBSS). Cells were incubated with 10 ␮mol/L immediately centrifuged at 4°C, and serum was frozen in Indo-1 AM for 30 minutes at 37°C, washed, resuspended aliquots at Ϫ80°C. ICP was diagnosed, as previously in HEPES-buffered HBSS, and incubated for another 30 described,18 in pregnant women with pruritus who had minutes at 25°C to allow dye hydrolysis. After another no rash in conjunction with increased serum liver wash step, cells were resuspended in HEPES-buffered BASIC–LIVER, transaminase and/or bile salt levels. Women were ex- HBSS. Analyses were performed in a NOVOstar analyzer BILIARY TRACT cluded if they had abnormal hepatitis serology (hepatitis (BMG Labtech GmbH, Offenburg, Germany; excitation, PANCREAS, AND A, B, and C) or extrahepatic biliary obstruction following 320 nm; emission, 405 nm and 520 nm). Cell suspensions ultrasonographic examination. Pregnant controls had no were allowed to adapt to 37°C for 10 minutes before history of liver dysfunction or
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