Horm Metab Res 2009; 41(4): 333-338
DOI: 10.1055/s-0028-1103300
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

Overexpression of Protein Kinase C-δ Plays a Crucial Role in Interleukin-6-Producing Pheochromocytoma Presenting with Acute Inflammatory Syndrome: A Case Report

H. Tokuda 1 , 2 , T. Hosoi 3 , K. Hayasaka 4 , K. Okamura 5 , N. Yoshimi 6 , O. Kozawa 2
  • 1Department of Clinical Laboratory, National Hospital for Geriatric Medicine, National Center for Geriatrics and Gerontology, Obu Aichi, Japan
  • 2Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
  • 3Department of Advanced Medicine, National Hospital for Geriatric Medicine, National Center for Geriatrics and Gerontology, Obu Aichi, Japan
  • 4Department of Clinical Radiology and National Hospital for Geriatric Medicine, National Center for Geriatrics and Gerontology, Obu Aichi, Japan
  • 5Department of Intensive Care, National Hospital for Geriatric Medicine, National Center for Geriatrics and Gerontology, Obu Aichi, Japan
  • 6Tumor Pathology, University of the Ryukyus Faculty of Medicine, Okinawa, Japan
Further Information

Publication History

received 04.07.2008

accepted 03.11.2008

Publication Date:
01 December 2008 (online)

Abstract

Pheochromocytomas are tumors that may produce a variety of substances in addition to catecholamines. To date, among several cases of systemic inflammatory syndrome associated with interleukin-6 (IL-6) secretion, IL-6-producing pheochromocytomas, have been reported. However, the mechanism underlying IL-6 oversecretion in these cases has not yet been clarified. This report describes a patient with pheochromocytoma who exhibited pyrexia and marked inflammatory signs including C-reactive protein elevation. The inflammatory symptoms were easily controlled by the administration of loxoprofen, a nonsteroidal anti-inflammatory drug. The plasma concentration of IL-6 and 11-d-TXB2, a stable metabolite of thromboxane A2 (TXA2), were significantly elevated in parallel with an elevation of norepinephrine in the samples obtained by selective venous sampling. A left adrenalectomy was performed, and the acute inflammatory symptoms naturally diminished without loxoprofen. Cultured tumor cells obtained from the resected specimen spontaneously released IL-6, and indomethacin inhibited the IL-6 release. According to a cDNA microarray analysis, mRNA of protein kinase C-δ (PKC-δ), prostaglandin D synthase, and arachidonate release-relating enzymes were significantly overexpressed in the tumor tissue in comparison to the adjacent nontumor tissue. The constitutive phosphorylation of PKC-δ was observed in the tumor tissue. These results strongly suggest that the systemic inflammatory syndrome in IL-6-producing pheochromocytoma, at least in part, is caused by the overexpression of PKC-δ, resulting in an excess of arachidonate derivatives such as prostaglandins.

References

  • 1 Pacak K, Keiser H, Eisenhofer G. Pheochromocytoma. In: DeGroot LJ, JL Jameson JL, eds. Endocrinology 5th edn. Phyladelphia: Elsevier 2006: 2501-2534
  • 2 Akira S, Taga T, Kishimoto T. Interleukin-6 in biology and medicine.  Adv Immunol. 1993;  54 1-78
  • 3 Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, Nakahata T, Kawai H, Tagoh H, Komori T, Kishimoto S, Hirano T, Kishimoto T. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease.  Blood. 1989;  74 1360-1367
  • 4 Tabibzadeh S, Poubouridis D, May LT, Sehgal PB. Interleukin-6 immunoreactivity in human tumors.  Am J Pathol. 1989;  135 427-433
  • 5 Päth G, Bornstein SR, Ehrhart-Bornstein M, Scherbaum WA. Interleukin-6 and the interleukin-6 receptor in the human adrenal gland; Expression and effects on steroidogenesis.  J Clin Endocrinol Metab. 1997;  82 2343-2349
  • 6 Fukumoto S, Matsumoto T, Harada S, Fujisaki J, Kawano M, Ogata E. Pheochromocytoma with pyrexia and marked inflammatory signs: a paraneoplastic syndrome with possible relation to interleukin-6 production.  J Clin Endocrinol Metab. 1991;  73 877-881
  • 7 Suzuki K, Miyashita A, Inoue Y, Iki S, Enomoto H, Takahashi Y, Takemura T. Interleukin-6 producing pheochromocytoma.  Acta Haematol. 1991;  85 217-219
  • 8 Takagi M, Egawa T, Motomura T, Sakuma-Mochizuki J, Nishimoto N, Kasayama S, Hayashi S, Koga M, Yoshizaki K, Yoshioka T, Okuyama A, Kishimoto T. Interleukin-6 secreting phaeochromocytoma associated with clinical markers of inflammation.  Clin Endocrinol (Oxford). 1997;  46 507-509
  • 9 Salahuddin A, Rohr-Kirchgraber T, Shekar R, West B, Loewenstein J. Interleukin-6 in the fever and multiorgan crisis of phochromocytoma.  Scand J Infect Dis. 1997;  29 640-642
  • 10 Shimizu C, Kubo M, Takano K, Takano A, Kijima H, Saji H, Katsuyama I, Sasano H, Koike T. Interleukin-6 (IL-6) producing pheochromocytoma presenting with acute inflammatory syndrome.  Clin Endocrinol (Oxford). 2001;  54 405-410
  • 11 Minetto M, Dovio A, Ventura M, Cappia S, Daffara F, Terzolo M, Angeli A. Interleukin-6 producing pheochromocytoma presenting with acute inflammatory syndrome.  J Endocrinol Invest. 2003;  26 453-457
  • 12 Kang JK, Lee WJ, Kim WB, Kim TY, Koh JM, Hong SJ, Huh J, Ro JY, Chi HS, Kim MS. Systemic inflammatory syndrome and hepatic inflammatory cell infiltration caused by an interleukin-6 producing pheochromocytoma.  Endocrine J. 2005;  52 193-198
  • 13 Trachte GJ, Hook PJ, Kemp JR, Acosta EP, Ziegler RJ. Thromboxane synthesis and actions in isolated adrenergic nerve (pheochromocytoma-12) cells.  J Pharmacol Exp Ther. 1988;  247 43-46
  • 14 Laemmli LK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4.  Nature. 1970;  227 680-685
  • 15 Kato K, Ito H, Hasegawa K, Inaguma Y, Kozawa O, Asano T. Modulation of the stress-induced synthesis of hsp27 and αB-crystallin by cyclic AMP in C6 rat glioma cells.  J Neurochem. 1996;  66 946-950
  • 16 Noda T, Kumada T, Takai S, Matsushima-Nishiwaki R, Yoshimi N, Yasuda E, Kato K, Toyoda H, Kaneoka Y, Yamaguchi A, Kozawa O. Expression levels of heat shock protein 20 decrease in parallel with tumor progression in patients with hepatocellular carcinoma.  Oncology Reports. 2007;  17 1309-1314
  • 17 Smith WL. The eicosanoids and their biochemical mechanisms of action.  Biochem J. 1989;  259 315-324
  • 18 Lee SD, Lee BD, Kim Y, Suh PG, Ryu SH. Bradykinin activates phospholiase D2 via protein kinase Cd in PC12 cells.  Neurosci Lett. 2000;  294 130-132
  • 19 Han JM, Kim JH, Lee BD, Lee SD, Kim Y, Jung YW, Lee S, Cho W, Ohba M, Kuroki T, Suh PG, Ryu SH. Phosphorylation-dependent regulation of phospholipase D2 by protein kinase C δ in rat pheochromocytoma PC12 cells.  J Biol Chem. 2003;  277 8290-8297
  • 20 Smyth EM, Burke A, FitzGerald GA. Lipid-derived autacoids: Eicosanoids and platelet-activating factor. In: Brunton LL, Lazo JS, Parker KL, eds. The Pharmacological Basis of Therapeutics 11th edn. New York: McGraw-Hill 2006: 653-670
  • 21 Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C.  Science. 1992;  258 607-614
  • 22 Singer WD, Brown A, Sternweis PC. Regulation of eukaryotic phosphatidylinositol-specific phospholipase C and phospholipase D.  Ann Rev Biochem. 1997;  66 475-509
  • 23 Keranen LM, Dutil EM, Newton AC. Protein kinase C is regulated in vivo by three functionally distinct phosphorylations.  Curr Biol. 1995;  5 1394-1403
  • 24 Clark JD, Schievella AR, Nalefski EA, Lin LL. Cytosolic phospholipase A2.  J Lipid Mediat Cell Signal. 1995;  12 83-117
  • 25 Smyth DC, Kerr C, Richards CD. Oncostatin M-induced IL-6 expression in murine fibroblasts requires the activation of protein kinase Cδ.  J Immunol. 2006;  177 8740-8747
  • 26 Vitale N, Caunomt AS, Chasserot-Golaz S, Du G, Wu S, Sciorra VA, Morris AJ, Frohman MA, Bader MF. Phospholipase D1: a key factor for the exocytotic machinery in neuroendocrine cells.  EMBO J. 2001;  20 2424-2434

Correspondence

H. Tokuda

Department of Clinical Laboratory

National Hospital for Geriatric Medicine

National Center for Geriatrics and Gerontology

Obu Aichi 474-8511

Japan

Phone: +81/562/46 23 11

Fax: +81/562/46 83 96

Email: tokuda@ncgg.go.jp