Abstract
Circulating interleukin-6 (IL-6) concentrations correlate with disease activity in severe inflammatory conditions, in sepsis and in some hematological malignancies. On the other hand, IL-6 is a potent stimulator of osteoclastogenesis and has been implicated as a contributory factor in the genesis of osteopenic conditions. We measured circulating IL-6 levels by a sensitive (detection limit of 10 U/ml) and specific bioassay in 103 patients with advanced cancer, including 41 with tumor-induced hypercalcemia before any specific hypocalcemic therapy. We related IL-6 concentrations to clinical features and to biochemical parameters of bone metabolism, including blood Ca, Ca2+, Pi, intact parathyroid hormone, parathyroid hormone-related protein, osteocalcin, 1,25-(OH)2-vitamin D and, as markers of bone resorption, the fasting urinary excretion of calcium (Ca/creatinine) and hydroxyproline. IL-6 levels were increased, i.e. detectable, in 23% of the patients, 8/41 (20%) hypercalcemic and 16/62 (26%) normocalcemic patients (NS); the distribution of the values was similar in the two groups. The presence of increased IL-6 concentrations was not related to any clinical characteristic, notably not to the survival nor to the existence of bone metastases, whether in hypercalcemic or normocalcemic patients; e.g., only 3/12 (25%) hypercalcemic subjects without bone metastases had elevated IL-6 levels. We found no significant correlations between IL-6 concentrations and any of the biochemical parameters studied. Hypercalcemic subjects with increased IL-6 had higher urinary Ca/creatinine levels than patients with normal IL-6 levels (P<0.005) but this was not the case in normocalcemic subjects. Mean concentrations of inflammatory or other bone metabolism markers were not significantly different between patients with normal or with elevated IL-6 levels. In summary, circulating IL-6 levels were increased in 23% of 103 patients with advanced cancer, but the frequency of increased IL-6 concentrations was not related to the presence of hypercalcemia or to any marker of calcium metabolism or bone turnover. The pathogenic importance of circulating IL-6 in patients with solid tumors remains to be demonstrated and our data indicate that increased circulating levels of IL-6, possibly reflecting the activation of the immune system, only contribute in a minor way to the osteolytic process in patients with tumor-induced hypercalcemia.
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Bataille R, Jourdan M, Zhang XG, Klein B (1989) Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest 84: 2008–2011
Beck JT, Hsu SM, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B (1994) Alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 330: 602–605
Black K, Garrett IR, Mundy GR (1991) Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thromobocytosis in tumor-bearing nude mice. Endocrinology 128: 2657–2659
Body JJ (1992) Bone metastases and tumor-induced hypercalcemia. Curr Opin Oncol 4: 624–631
Body JJ, Delmas PD (1992) Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia. J Clin Endocrinol Metab 74: 471–475
Body JJ, Cleeren A, Pot M, Borkowski A (1986) Serum osteocalcin (BGP) in tumor-associated hypercalcemia. J Bone Miner Res 1: 523–527
Body JJ, Dumon JC, Seraj F, Cleeren A (1992) Recovery of parathyroid hormone secretion during correction of tumor-associated hypercalcemia. J Clin Endocrinol Metab 74: 1385–1388
Body JJ, Dumon JC, Thirion M, Cleeren A (1993) Circulating PTHrP concentrations in tumor-induced hypercalcemia: influence on the response to bisphosphonate and changes after therapy. J Bone Miner Res 8: 701–706.
Body JJ, Dumon JC (1994) Treatment of tumor-induced hypercalcaemia with the bisphosphonate pamidronate: dose-response relationship and influence of the tumor type. Ann Oncol 5: 359–363
Burits WJ (1992) Parathyroid hormone-related protein: structure, function and measurement. Clin Chem 38: 2171–2183
Calandra T, Gerain J, Heumann D, Baumgartner JD, Glauser MP and the Swiss-Dutch J5 Immunoglobulin Study Group (1991) High circulating levels of interleukin-6 in patients with septic shock: evolution during sepsis, prognostic value, and interplay with other cytokines. Am J Med 91: 23–29
Fukumoto S, Matsumoto T, Harada SI, Fujisaki J, Kawano M, Ogata E (1991) Pheochromocytoma with pyrexia and marked inflammatory signs: a paraneoplastic syndrome with possible relation to interleukin-6 production. J Clin Endocrinol Metab 73: 877–881
Gabay C, Roux-Lombard P, Moerloose P de, Dayer JM, Vischer T, Guerne PA (1993) Absence of correlation between interleukin 6 and C-reactive protein blood levels in systemic lupus erythematosus compared with rheumatoid arthritis. J Rheumatol 20: 815–821
Gaillard JP, Bataille R, Brailly H, Zuber C, Yasukawa K, Attal M, Marvo N, Taga T, Kishimoto T, Klein B (1993) Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol 23: 820–824
Gallo O, Gori AM, Attanasio M, Martini F, Fini-Storchi O, Abbate R (1992) Interleukin-6 serum level and monocyte production in head and neck cancer. Br J Cancer 65: 479–480
Garrett IR (1993) Bone destruction in cancer. Semin Oncol 20: 4–9
Grill V, Ho P, Body JJ, Johanson N, Lee SC, Kukreja SC, Moseley JM, Martin TJ (1991) Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breas cancer. J Clin Endocrinol Metab 73: 1309–1315
Hack CE, De Groot ER, Felt-Bersma RJF, Nuijens JH, Strack Van Schijndel RJM, Eerenberg-Belmer AJM, Thijs LG, Aarden LA (1989) Increased plasma levels of interleukin-6 in sepsis. Blood 74: 1704–1710
Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T (1988) Autocrine generation and essential requirement of BSF-2/JL-6 for human multiple myelomas. Nature 332: 83–85
Kurihara N, Bertolini D, Suda T, Akiyama Y, Roodman GD (1990) IL-6 stimulates osteoclast-like multinucleated cell formation in long term human marrow cultures by inducing IL-1 release. J Immunol 144:4226–4230
Kurzrock R, Redman J, Cabanillas F, Jones, D, Rothberg J, Talpaz M (1993) Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin's disease and with B symptoms. Cancer Res 53: 2118–2122
Lorenzo JA (1991) The role of cytokines in the regulation of local bone resorption. Crit Rev Immunol 11: 195–213
Madhok R, Crilly A, Watson J, Capell HA (1993) Serum interleukin 6 levels in rheumatoid arthritis: correlations with clinical and laboratory indices of disease activity. Ann Rheum Dis 52: 232–234
Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T (1989) Interleukin-6 functions as an in vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 250: 607–610
Nachbaur DM, Herold M, Maneschg A, Huber H (1991) Serum levels of interleukin-6 in multiple myeloma and other hematological disorders: correlation with disease activity and other prognostic parameters. Ann Hematol 62: 54–58
Pacifici R, Brown C, Puscheck E, Friedrich E, Slatopolsky E, Maggio D, McCracken R, Avioli LV (1991) Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci USA 88: 5134–5138
Roodman GD (1992) Interleukin-6: an osteotropic factor? J Bone Miner Res 7: 475–478
Tabibzadeh SS, Poubouridis D, May LT, Sehgal PB (1989) Interleukin-6 immunoreactivity in human tumors. Am J Pathol 135: 427–433
Van Snick J (1990) Interleukin-6: an overview. Annu Rev Immunol 8: 253–278
Van Snick J, Cayphas S, Vink A, Uytenhove C, Coulie PG, Rubira MR, Simpson RJ (1986) Purification and NH2-terminal amino acid sequences of a T-cell-derived lymphokine with growth factor activity for B-cell hybridomas. Proc Natl Acad Sci USA 83: 9679–9683
Watson JM, Sensintaffar JL, Berek JS, Martinez-Maza O (1990) Constitutive production of interleukin-6 ovarian cancer cell lines and by primary ovarian tumor cultures. Cancer Res 50: 6959–6965
Yoneda T, Nakai M, Moriyama K, Scott L, Ida N, Kunitomo T, Mundy GR (1993) Neutralizing antibodies to human interleukin 6 reverse hypercalcemia associated with a human squamous carcinoma. Cancer Res 53: 737–740
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Vanderschueren, B., Dumon, J.C., Oleffe, V. et al. Circulating concentrations of interleukin-6 in cancer patients and their pathogenic role in tumor-induced hypercalcemia. Cancer Immunol Immunother 39, 286–290 (1994). https://doi.org/10.1007/BF01519980
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DOI: https://doi.org/10.1007/BF01519980