High Circulating Levels of Biologically Inactive IL-6/SIL-6 Receptor Complexes in Systemic Juvenile Idiopathic Arthritis: Evidence for Serum Factors Interfering with the Binding to Gp130

Overview

Journal Clin Exp Immunol

Publisher Oxford University Press

Specialty Allergy & Immunology

Date 2003 Feb 4

PMID 12562400

Citations 5

Authors

P Pignatti

L Ciapponi

P Galle

M B Hansen

M Massa

C Meazza

G Paonessa

D Novick

G Ciliberto

A Martini

F De Benedetti

Affiliations

Soon will be listed here.

Abstract

We previously demonstrated that high levels of IL-6/sIL-6R complexes are present in sera of patients with systemic juvenile idiopathic arthritis (s-JIA) and that the amount of IL-6 estimated in the IL-6/sIL-6R complexes is markedly higher than that measured by the B9 assay. Here, we show that two additional bioassays, employing human myeloma XG-1 cells and human hepatoma Hep3B cells, detected serum IL-6 levels similar to those measured by the B9 assay and approximately 10-fold lower than the IL-6 levels estimated to be present in the IL-6/sIL-6R complex. Using an assay for the measurement of the amount of circulating IL-6 complexed with the sIL-6R and available for binding to gp130 (gp130 binding activity), we show that the IL-6/gp130 binding activity is similar to that detected by the bioassays and again significantly lower than that estimated to be present in the IL-6/sIL-6R complex. Addition of recombinant human IL-6 (rhIL-6) to sera of patients or controls results in a markedly lower increase in the gp130 binding activity in patients than in controls. Moreover, sera from s-JIA patients inhibited in a dose dependent manner the gp130 binding activity assay. These results show that sera from patients with s-JIA contain a factor, or factors, that inhibit(s) the binding of the IL-6/sIL-6R complex to gp130. This inhibitory activity does not appear to be due to soluble gp130, C-reactive protein or autoantibodies to IL-6.

Citing Articles

Targeting interleukin-6 for noninfectious uveitis.

Lin P Clin Ophthalmol. 2015; 9:1697-702.

PMID: 26392750 PMC: 4574854. DOI: 10.2147/OPTH.S68595.

Interleukin-6 in surgery, trauma, and critical care part II: clinical implications.

Jawa R, Anillo S, Huntoon K, Baumann H, Kulaylat M J Intensive Care Med. 2011; 26(2):73-87.

PMID: 21464062 PMC: 6223019. DOI: 10.1177/0885066610384188.

Analytic review: Interleukin-6 in surgery, trauma, and critical care: part I: basic science.

Jawa R, Anillo S, Huntoon K, Baumann H, Kulaylat M J Intensive Care Med. 2011; 26(1):3-12.

PMID: 21262749 PMC: 6209321. DOI: 10.1177/0885066610395678.

Leptin resistance: a possible interface of inflammation and metabolism in obesity-related cardiovascular disease.

Martin S, Qasim A, Reilly M J Am Coll Cardiol. 2008; 52(15):1201-10.

PMID: 18926322 PMC: 4556270. DOI: 10.1016/j.jacc.2008.05.060.

Blood and synovial fluid cytokine signatures in patients with juvenile idiopathic arthritis: a cross-sectional study.

de Jager W, Hoppenreijs E, Wulffraat N, Wedderburn L, Kuis W, Prakken B Ann Rheum Dis. 2006; 66(5):589-98.

PMID: 17170049 PMC: 1954617. DOI: 10.1136/ard.2006.061853.

References

Rose-John S, Heinrich P . Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J. 1994; 300 ( Pt 2):281-90. PMC: 1138158. DOI: 10.1042/bj3000281. View

Klouche M, Bhakdi S, Hemmes M, Rose-John S . Novel path to activation of vascular smooth muscle cells: up-regulation of gp130 creates an autocrine activation loop by IL-6 and its soluble receptor. J Immunol. 1999; 163(8):4583-9. View

May L, Patel K, Garcia D, Ndubuisi M, Ferrone S, Mittelman A . Sustained high levels of circulating chaperoned interleukin-6 after active specific cancer immunotherapy. Blood. 1994; 84(6):1887-95. View

Savino R, Ciapponi L, Lahm A, Demartis A, Cabibbo A, Toniatti C . Rational design of a receptor super-antagonist of human interleukin-6. EMBO J. 1994; 13(24):5863-70. PMC: 395561. DOI: 10.1002/j.1460-2075.1994.tb06931.x. View

Hansen M, Svenson M, Abell K, Yasukawa K, Diamant M, Bendtzen K . Influence of interleukin-6 (IL-6) autoantibodies on IL-6 binding to cellular receptors. Eur J Immunol. 1995; 25(2):348-54. DOI: 10.1002/eji.1830250207. View

Paonessa G, Graziani R, DE SERIO A, Savino R, Ciapponi L, Lahm A . Two distinct and independent sites on IL-6 trigger gp 130 dimer formation and signalling. EMBO J. 1995; 14(9):1942-51. PMC: 398293. DOI: 10.1002/j.1460-2075.1995.tb07186.x. View

Mihara M, Moriya Y, Kishimoto T, Ohsugi Y . Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol. 1995; 34(4):321-5. DOI: 10.1093/rheumatology/34.4.321. View

Hilbert D, Kopf M, Mock B, Kohler G, Rudikoff S . Interleukin 6 is essential for in vivo development of B lineage neoplasms. J Exp Med. 1995; 182(1):243-8. PMC: 2192088. DOI: 10.1084/jem.182.1.243. View

Kishimoto T, Akira S, Narazaki M, Taga T . Interleukin-6 family of cytokines and gp130. Blood. 1995; 86(4):1243-54. View

10.

Lu Z, Brailly H, Wijdenes J, Bataille R, Rossi J, Klein B . Measurement of whole body interleukin-6 (IL-6) production: prediction of the efficacy of anti-IL-6 treatments. Blood. 1995; 86(8):3123-31. View

11.

Ledur A, Fitting C, David B, Hamberger C, Cavaillon J . Variable estimates of cytokine levels produced by commercial ELISA kits: results using international cytokine standards. J Immunol Methods. 1995; 186(2):171-9. DOI: 10.1016/0022-1759(95)00184-c. View

12.

Peters M, Jacobs S, Ehlers M, Vollmer P, Mullberg J, Wolf E . The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med. 1996; 183(4):1399-406. PMC: 2192475. DOI: 10.1084/jem.183.4.1399. View

13.

Tajima S, Tsuji K, Ebihara Y, Sui X, Tanaka R, Muraoka K . Analysis of interleukin 6 receptor and gp130 expressions and proliferative capability of human CD34+ cells. J Exp Med. 1996; 184(4):1357-64. PMC: 2192851. DOI: 10.1084/jem.184.4.1357. View

14.

Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P . Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997; 6(3):315-25. DOI: 10.1016/s1074-7613(00)80334-9. View

15.

Nishimoto N, Sasai M, Shima Y, Nakagawa M, Matsumoto T, Shirai T . Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood. 1999; 95(1):56-61. View

16.

Atreya R, Mudter J, Finotto S, Mullberg J, Jostock T, Wirtz S . Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo. Nat Med. 2000; 6(5):583-8. DOI: 10.1038/75068. View

17.

Tanaka M, Kishimura M, Ozaki S, Osakada F, Hashimoto H, Okubo M . Cloning of novel soluble gp130 and detection of its neutralizing autoantibodies in rheumatoid arthritis. J Clin Invest. 2000; 106(1):137-44. PMC: 314355. DOI: 10.1172/JCI7479. View

18.

Jostock T, Mullberg J, Ozbek S, Atreya R, Blinn G, Voltz N . Soluble gp130 is the natural inhibitor of soluble interleukin-6 receptor transsignaling responses. Eur J Biochem. 2000; 268(1):160-7. DOI: 10.1046/j.1432-1327.2001.01867.x. View

19.

Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T . Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989; 58(3):573-81. DOI: 10.1016/0092-8674(89)90438-8. View

20.

Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K . Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood. 1989; 74(4):1360-7. View