The Brady Urological Institute, Johns Hopkins Bayview Medical Center, 301 Building, Room 3104, 4940 Eastern Ave., Baltimore, Maryland 21224, USASearch for more papers by this author

Kazutoshi Fujita,

Kazutoshi Fujita

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD

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Charles M. Ewing,

Charles M. Ewing

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD

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William B. Isaacs,

William B. Isaacs

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD

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Christian P. Pavlovich,

Corresponding Author

Christian P. Pavlovich

[email protected]

Brady Urological Institute, Johns Hopkins Medical Institutions, Baltimore, MD

Tel.: 410-550-0013, Fax: 410-550-3341

The Brady Urological Institute, Johns Hopkins Bayview Medical Center, 301 Building, Room 3104, 4940 Eastern Ave., Baltimore, Maryland 21224, USASearch for more papers by this author

First published: 28 September 2010

https://doi.org/10.1002/ijc.25705

Citations: 35

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Abstract

Cytokines may play a role in the initiation and progression of prostate cancer. A cytokine antibody array was previously applied to prostatic fluid obtained from patients with prostate cancer, and interleukin 18 binding protein (IL-18BP), a potent inhibitor of interleukin 18, was noted to be significantly upregulated in cases with large volume disease. We sought to further characterize the association of IL-18BP with prostate cancer and determine whether IL-18BP levels in patient serum and urine samples had clinical relevance. IL-18BP was expressed and secreted by the prostate cancer cell lines DU145 and PC3 but not by LNCaP and CWR22, upon interferon-γ (IFN-γ) stimulation. IFN-γ-induced secretion of IL-18BP was enhanced by added TNF-α, IFN-α and IFN-β. The IL-18BP secreted from DU145 and PC3 functionally inhibited IL-18. Immunohistochemical analyses showed positive IL-18BP staining in prostate cancer cells as well as in macrophages in radical prostatectomy specimens. Significant differences in urinary IL-18BP levels (normalized by total protein) collected post-DRE were found between cases with and without cancer on biopsy (p = 0.02) and serum IL-18BP levels correlated with Gleason score (p = 0.03). Our finding of elevated IL-18BP secretion from prostate cancer cells suggests an attempt by cancer to escape immune surveillance. IL-18BP merits further study as a marker of aggressive prostate cancer and as a therapeutic target.

References

1 Cohen RJ, Shannon BA, McNeal JE, Shannon T, Garrett KL. Propionibacterium acnes associated with inflammation in radical prostatectomy specimens: a possible link to cancer evolution? J Urol 2005; 173: 1969–74.
10.1097/01.ju.0000158161.15277.78
PubMed Web of Science® Google Scholar
2 De Marzo A, Platz E, Sutcliffe S, Xu J, Grönberg H, Drake C, Nakai Y, Isaacs W, Nelson W. Inflammation in prostate carcinogenesis. Nat Rev Immunol 2007; 7: 256–69.
CAS PubMed Web of Science® Google Scholar
3 Lin WW, Karin M. A cytokine-mediated link between innate immunity, inflammation, and cancer. J Clin Invest 2007; 117: 1175–83.
10.1172/JCI31537
CAS PubMed Web of Science® Google Scholar
4 de Visser KE, Eichten A, Coussens LM. Paradoxical roles of the immune system during cancer development. Nat Rev Cancer 2006; 6: 24–37.
10.1038/nrc1782
CAS PubMed Web of Science® Google Scholar
5 Swann JB, Smyth MJ. Immune surveillance of tumors. J Clin Invest 2007; 117: 1137–46.
10.1172/JCI31405
CAS PubMed Web of Science® Google Scholar
6 Fujita K, Ewing CM, Sokoll LJ, Elliott DJ, Cunningham M, De Marzo AM, Isaacs WB, Pavlovich CP. Cytokine profiling of prostatic fluid from cancerous prostate glands identifies cytokines associated with extent of tumor and inflammation. Prostate 2008; 68: 872–82.
10.1002/pros.20755
CAS PubMed Web of Science® Google Scholar
7 Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M. Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 1999; 10: 127–36.
10.1016/S1074-7613(00)80013-8
CAS PubMed Web of Science® Google Scholar
8 Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol 2001; 19: 423–74.
10.1146/annurev.immunol.19.1.423
CAS PubMed Web of Science® Google Scholar
9 Paulukat J, Bosmann M, Nold M, Garkisch S, Kampfer H, Frank S, Raedle J, Zeuzem S, Pfeilschifter J, Muhl H. Expression and release of IL-18 binding protein in response to IFN-gamma. J Immunol 2001; 167: 7038–43.
10.4049/jimmunol.167.12.7038
CAS PubMed Web of Science® Google Scholar
10 Muhl H, Kampfer H, Bosmann M, Frank S, Radeke H, Pfeilschifter J. Interferon-gamma mediates gene expression of IL-18 binding protein in nonleukocytic cells. Biochem Biophys Res Commun 2000; 267: 960–3.
10.1006/bbrc.1999.2064
CAS PubMed Web of Science® Google Scholar
11 Corbaz A, ten Hove T, Herren S, Graber P, Schwartsburd B, Belzer I, Harrison J, Plitz T, Kosco-Vilbois MH, Kim SH, Dinarello CA, Novick D, et al. IL-18-binding protein expression by endothelial cells and macrophages is up-regulated during active Crohn's disease. J Immunol 2002; 168: 3608–16.
10.4049/jimmunol.168.7.3608
CAS PubMed Web of Science® Google Scholar
12 Novick D, Schwartsburd B, Pinkus R, Suissa D, Belzer I, Sthoeger Z, Keane WF, Chvatchko Y, Kim SH, Fantuzzi G, Dinarello CA, Rubinstein M. A novel IL-18BP ELISA shows elevated serum IL-18BP in sepsis and extensive decrease of free IL-18. Cytokine 2001; 14: 334–42.
10.1006/cyto.2001.0914
CAS PubMed Web of Science® Google Scholar
13 Veenstra KG, Jonak ZL, Trulli S, Gollob JA. IL-12 induces monocyte IL-18 binding protein expression via IFN-gamma. J Immunol 2002; 168: 2282–7.
10.4049/jimmunol.168.5.2282
CAS PubMed Web of Science® Google Scholar
14 Klampfer L, Huang J, Swaby LA, Augenlicht L. Requirement of histone deacetylase activity for signaling by STAT1. J Biol Chem 2004; 279: 30358–68.
10.1074/jbc.M401359200
CAS PubMed Web of Science® Google Scholar
15 Bachmann M, Paulukat J, Pfeilschifter J, Muhl H. Molecular mechanisms of IL-18BP regulation in DLD-1 cells: pivotal direct action of the STAT1/GAS axis on the promoter level. J Cell Mol Med 2009; 13: 1987–94.
10.1111/j.1582-4934.2008.00604.x
CAS PubMed Web of Science® Google Scholar
16 Lapointe J, Li C, Higgins JP, van de Rijn M, Bair E, Montgomery K, Ferrari M, Egevad L, Rayford W, Bergerheim U, Ekman P, DeMarzo AM, et al. Gene expression profiling identifies clinically relevant subtypes of prostate cancer. Proc Natl Acad Sci USA 2004; 101: 811–6.
10.1073/pnas.0304146101
CAS PubMed Web of Science® Google Scholar
17 Kim SH, Eisenstein M, Reznikov L, Fantuzzi G, Novick D, Rubinstein M, Dinarello CA. Structural requirements of six naturally occurring isoforms of the IL-18 binding protein to inhibit IL-18. Proc Natl Acad Sci USA 2000; 97: 1190–5.
10.1073/pnas.97.3.1190
CAS PubMed Web of Science® Google Scholar
18 Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006; 6: 836–48.
10.1038/nri1961
CAS PubMed Web of Science® Google Scholar
19 Zhang B, Karrison T, Rowley DA, Schreiber H. IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers. J Clin Invest 2008; 118: 1398–404.
10.1172/JCI33522
CAS PubMed Web of Science® Google Scholar
20 Ikeda H, Old LJ, Schreiber RD. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002; 13: 95–109.
10.1016/S1359-6101(01)00038-7
CAS PubMed Web of Science® Google Scholar
21 Kaser A, Novick D, Rubinstein M, Siegmund B, Enrich B, Koch RO, Vogel W, Kim SH, Dinarello CA, Tilg H. Interferon-alpha induces interleukin-18 binding protein in chronic hepatitis C patients. Clin Exp Immunol 2002; 129: 332–8.
10.1046/j.1365-2249.2002.01911.x
CAS PubMed Web of Science® Google Scholar
22 Xiang Y, Moss B. IL-18 binding and inhibition of interferon gamma induction by human poxvirus-encoded proteins. Proc Natl Acad Sci USA 1999; 96: 11537–42.
10.1073/pnas.96.20.11537
CAS PubMed Web of Science® Google Scholar
23 Robertson MJ, Mier JW, Logan T, Atkins M, Koon H, Koch KM, Kathman S, Pandite LN, Oei C, Kirby LC, Jewell RC, Bell WN, et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin Cancer Res 2006; 12: 4265–73.
10.1158/1078-0432.CCR-06-0121
CAS PubMed Web of Science® Google Scholar
24 Robertson MJ, Kirkwood JM, Logan TF, Koch KM, Kathman S, Kirby LC, Bell WN, Thurmond LM, Weisenbach J, Dar MM. A dose-escalation study of recombinant human interleukin-18 using two different schedules of administration in patients with cancer. Clin Cancer Res 2008; 14: 3462–9.
10.1158/1078-0432.CCR-07-4740
CAS PubMed Web of Science® Google Scholar
25 Lebel-Binay S, Thiounn N, De Pinieux G, Vieillefond A, Debre B, Bonnefoy JY, Fridman WH, Pages F. IL-18 is produced by prostate cancer cells and secreted in response to interferons. Int J Cancer 2003; 106: 827–35.
10.1002/ijc.11285
CAS PubMed Web of Science® Google Scholar
26 Mazodier K, Marin V, Novick D, Farnarier C, Robitail S, Schleinitz N, Veit V, Paul P, Rubinstein M, Dinarello CA, Harle JR, Kaplanski G. Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome. Blood 2005; 106: 3483–9.
10.1182/blood-2005-05-1980
CAS PubMed Web of Science® Google Scholar
27 Nickel JC, Shoskes D, Wang Y, Alexander RB, Fowler JE, Jr, Zeitlin S, O'Leary MP, Pontari MA, Schaeffer AJ, Landis JR, Nyberg L, Kusek JW, et al. How does the pre-massage and postmassage 2-glass test compare to the Meares-Stamey 4-glass test in men with chronic prostatitis/chronic pelvic pain syndrome? J Urol 2006; 176: 119–24.
10.1016/S0022-5347(06)00498-8
PubMed Web of Science® Google Scholar

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Volume129, Issue2

15 July 2011

Pages 424-432

Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status

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Immunomodulatory IL-18 binding protein is produced by prostate cancer cells and its levels in urine and serum correlate with tumor status

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