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Bacillus Calmette-Guérin potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients

  • Original Articles
  • BCG, IL-1, IL-6, TNFα, IL-1 Receptor Antagonist, Macrophages, LPS, Bladder Cancer Acute-Phase Proteins
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Abstract

During the past decade, particular attention has been focused on treatment of bladder cancer patients with the bacterial agent bacillus Calmette-Guérin (BCG). In these studies, bladder cancer patients were instilled with BCG (75mg/50ml) once per week for 6 weeks, 1–2 weeks following trans-urethreal resection of the bladder. Cystoscopy was performed after 6 weeks and, unless tumor progression was present, monthly treatments were given for 1 year. Blood was drawn 2 h after the last instillation, and monocytes were isolated (5×106 cells/ml) and treated, or not, with lipopolysaccharide (LPS) (20 μg/ml) for tumor necrosis factor α (TNFα), interleukin-1α (IL-1α) and interleukin-6 (IL-6) release. The levels of monokines were determined by a monokine-specific enzyme-linked immunosorbent assay. Out results clearly show that, after 18 h incubation, macrophages from BCG-treated bladder cancer patients produced from 2.8- to 1.9-fold and from 2.0- to 1.3-fold greater amounts of TNFα and IL-1α respectively, compared to macrophages from healthy controls, 5-fold higher than bladder cancer patients not treated with BCG. IL-6 was not affected. In another set of experiments macrophages (5×106 cells/ml) from healthy subjects were pretreated, or not, with BCG (100 μg/ml) overnight and treated, or not, with LPS 20 μg/ml alone and in combination with interleukin-1 receptor antagonist (IL-1ra) 250 ng/ml. Macrophages treated with BCG had a strong stimulatory effect on IL-1α release (9.45 ng/ml) while LPS was less effective (3.59 ng/ml). The combination of BCG plus LPS produced an additive effect on IL-1α release (13.71 ng/ml) compared to the effect of the compound alone. The addition of IL-1ra (250 ng/ml) to BCG was not effective, while when IL-1ra was added to BCG plus LPS only a partial inhibition of IL-1α release was found (9.83 ng/ml), compared to BCG plus LPS without IL-1ra (13.71 ng/ml). These effects seem to be related to the inhibition of IL-1α stimulated with LPS, but not BCG. The priming effect of BCG exerted on LPS-stimulated monocyte production of TNFα and IL-1α from bladder cancer patients led us to study the possible modulation of fibrinogen and C-reactive protein in the serum of BCG-treated cancer patients. The plasma levels of fibrinogen and C-reactive protein were higher (approximately twice) in BCG-treated patients compared to values obtained in untreated patients or healthy controls. We conclude that the beneficial immunotherapeutic effects of BCG in bladder cancer patients are related to its capacity to prime macrophages to enhance the release of TNFα and IL-1α, but not IL-6 in response to physiological secondary stimuli, or through the direct stimulation of BCG on IL-1α or TNFα, which are directly involved in the killing of cancer cells. Moreover, the increase of IL-1α or TNFα in BCG bladder cancer patients may lead to high plasma levels of fibrinogen and C-reactive protein, two proteins responsible for the acute-phase response.

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Authors and Affiliations

  1. Immunology Division, Institute of Experimental Medicine, University of Chieti Medical School, Via dei Vestini, 1-66100, Chieti, Italy

    Pio Conti, Marcella Reale, Renato C. Barbacane & Fernanda C. Placido

  2. Urology Division, Institute of Surgery, University of Chieti Medical School, 1-66100, Chieti, Italy

    Michele Nicolai, Romina Iantorno & Raffaele Tenaglia

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  1. Pio Conti
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  2. Marcella Reale
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  3. Michele Nicolai
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  4. Renato C. Barbacane
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  5. Fernanda C. Placido
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  6. Romina Iantorno
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  7. Raffaele Tenaglia
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Conti, P., Reale, M., Nicolai, M. et al. Bacillus Calmette-Guérin potentiates monocyte responses to lipopolysaccharide-induced tumor necrosis factor and interleukin-1, but not interleukin-6 in bladder cancer patients. Cancer Immunol Immunother 38, 365–371 (1994). https://doi.org/10.1007/BF01517205

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  • DOI: https://doi.org/10.1007/BF01517205

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