Niemann-pick Type C2 Deficiency in Human Fibroblasts Confers Robust and Selective Activation of Prostaglandin E2 Biosynthesis

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2013 Jul 2

PMID 23814065

Citations 1

Authors

Andrey Frolov

Hua Dong

Min Jiang

Lihua Yang

Erik C Cook

Rahul Matnani

Bruce D Hammock

Leslie J Crofford

Affiliations

Soon will be listed here.

Abstract

Activated fibroblasts, also known as myofibroblasts, are mediators of several major human pathologies including proliferative fibrotic disorders, invasive tumor growth, rheumatoid arthritis, and atherosclerosis. We previously identified Niemann-Pick type C2 (NPC2) protein as a negative regulator of fibroblast activation (Csepeggi, C., Jiang, M., Kojima, F., Crofford, L. J., and Frolov, A. (2011) J. Biol. Chem. 286, 2078-2087). Here we report that NPC2-deficiency leads to a dramatic up-regulation of the arachidonic acid (AA) metabolic pathway in human fibroblasts. The major enzymes in this pathway, cPLA2 type IVA, COX-2, and mPGES-1, were dramatically up-regulated at both the transcriptional and translational levels. The specific phenotypic changes resulted in a >10-fold increase in the production and secretion of a key modulator of inflammation and immunity, prostaglandin E2. More importantly, AA metabolome profiling by liquid chromatography/tandem mass-spectrometry revealed the very specific nature of prostaglandin E2 up-regulation as the other analyzed AA metabolites derived from the COX-2, cytochrome P450, 5/15-lipoxygenase, and non-enzymatic oxidative pathways were mostly down-regulated. Blocking activity of cPLA2 efficiently suppressed expression of inflammatory cytokines, IL-1β and IL-6, thereby identifying cPLA2 as an important regulator of the inflammatory program in NPC2-null cells. Altogether, these studies highlight NPC2 as a specific regulator of AA metabolism and inflammation that suggests potential for NPC2 protein or its related signaling in the treatment of inflammatory diseases characterized by the presence of activated fibroblasts.

Citing Articles

Niemann-Pick C2 Proteins: A New Function for an Old Family.

Zhu J, Guo M, Ban L, Song L, Liu Y, Pelosi P Front Physiol. 2018; 9:52.

PMID: 29472868 PMC: 5810286. DOI: 10.3389/fphys.2018.00052.

References

Hinz B, Phan S, Thannickal V, Prunotto M, Desmouliere A, Varga J . Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol. 2012; 180(4):1340-55. PMC: 3640252. DOI: 10.1016/j.ajpath.2012.02.004. View

Seymour M, Zaidi N, Hollenberg M, MacNaughton W . PAR1-dependent and independent increases in COX-2 and PGE2 in human colonic myofibroblasts stimulated by thrombin. Am J Physiol Cell Physiol. 2002; 284(5):C1185-92. DOI: 10.1152/ajpcell.00126.2002. View

Okamura N, Kiuchi S, Tamba M, Kashima T, Hiramoto S, Baba T . A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol. Biochim Biophys Acta. 1999; 1438(3):377-87. DOI: 10.1016/s1388-1981(99)00070-0. View

Bhattacharyya S, Wei J, Varga J . Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2011; 8(1):42-54. PMC: 3954787. DOI: 10.1038/nrrheum.2011.149. View

Csepeggi C, Jiang M, Frolov A . Somatic cell plasticity and Niemann-pick type C2 protein: adipocyte differentiation and function. J Biol Chem. 2010; 285(39):30347-54. PMC: 2943299. DOI: 10.1074/jbc.M110.135939. View

Lloyd-Evans E, Morgan A, He X, Smith D, Elliot-Smith E, Sillence D . Niemann-Pick disease type C1 is a sphingosine storage disease that causes deregulation of lysosomal calcium. Nat Med. 2008; 14(11):1247-55. DOI: 10.1038/nm.1876. View

Naureckiene S, Sleat D, Lackland H, Fensom A, Vanier M, WATTIAUX R . Identification of HE1 as the second gene of Niemann-Pick C disease. Science. 2000; 290(5500):2298-301. DOI: 10.1126/science.290.5500.2298. View

Coen M, Gabbiani G, Bochaton-Piallat M . Myofibroblast-mediated adventitial remodeling: an underestimated player in arterial pathology. Arterioscler Thromb Vasc Biol. 2011; 31(11):2391-6. DOI: 10.1161/ATVBAHA.111.231548. View

Freeman E, Ruehr M, Dorman R . ANG II-induced translocation of cytosolic PLA2 to the nucleus in vascular smooth muscle cells. Am J Physiol. 1998; 274(1):C282-8. DOI: 10.1152/ajpcell.1998.274.1.C282. View

10.

Nah S, Won H, Ha E, Kang I, Cho H, Hur S . Epidermal growth factor increases prostaglandin E2 production via ERK1/2 MAPK and NF-kappaB pathway in fibroblast like synoviocytes from patients with rheumatoid arthritis. Rheumatol Int. 2009; 30(4):443-9. DOI: 10.1007/s00296-009-0976-6. View

11.

Petrovic N, Knight D, Bomalaski J, Thompson P, Misso N . Concomitant activation of extracellular signal-regulated kinase and induction of COX-2 stimulates maximum prostaglandin E2 synthesis in human airway epithelial cells. Prostaglandins Other Lipid Mediat. 2006; 81(3-4):126-35. DOI: 10.1016/j.prostaglandins.2006.08.006. View

12.

Rudnick J, Arendt L, Klebba I, Hinds J, Iyer V, Gupta P . Functional heterogeneity of breast fibroblasts is defined by a prostaglandin secretory phenotype that promotes expansion of cancer-stem like cells. PLoS One. 2011; 6(9):e24605. PMC: 3177828. DOI: 10.1371/journal.pone.0024605. View

13.

Bartok B, Firestein G . Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 2010; 233(1):233-55. PMC: 2913689. DOI: 10.1111/j.0105-2896.2009.00859.x. View

14.

Csepeggi C, Jiang M, Kojima F, Crofford L, Frolov A . Somatic cell plasticity and Niemann-Pick type C2 protein: fibroblast activation. J Biol Chem. 2010; 286(3):2078-87. PMC: 3023505. DOI: 10.1074/jbc.M110.135897. View

15.

Smith R . Modulation of phagocytosis by and lysosomal enzyme secretion from guinea-pig neutrophils: effect of nonsteroid anti-inflammatory agents and prostaglindins. J Pharmacol Exp Ther. 1977; 200(3):647-57. View

16.

Leizer T, Clarris B, Ash P, Van Damme J, Saklatvala J, Hamilton J . Interleukin-1 beta and interleukin-1 alpha stimulate the plasminogen activator activity and prostaglandin E2 levels of human synovial cells. Arthritis Rheum. 1987; 30(5):562-6. DOI: 10.1002/art.1780300511. View

17.

Sa G, Murugesan G, Jaye M, Ivashchenko Y, Fox P . Activation of cytosolic phospholipase A2 by basic fibroblast growth factor via a p42 mitogen-activated protein kinase-dependent phosphorylation pathway in endothelial cells. J Biol Chem. 1995; 270(5):2360-6. DOI: 10.1074/jbc.270.5.2360. View

18.

Frolov A, Zielinski S, Crowley J, Dudley-Rucker N, Schaffer J, Ory D . NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. J Biol Chem. 2003; 278(28):25517-25. DOI: 10.1074/jbc.M302588200. View

19.

Glover S, de Carvalho M, Bayburt T, Jonas M, Chi E, Leslie C . Translocation of the 85-kDa phospholipase A2 from cytosol to the nuclear envelope in rat basophilic leukemia cells stimulated with calcium ionophore or IgE/antigen. J Biol Chem. 1995; 270(25):15359-67. DOI: 10.1074/jbc.270.25.15359. View

20.

Klein A, Amigo L, Retamal M, Morales M, Miquel J, Rigotti A . NPC2 is expressed in human and murine liver and secreted into bile: potential implications for body cholesterol homeostasis. Hepatology. 2005; 43(1):126-33. DOI: 10.1002/hep.20985. View