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

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 (75 mg/50 ml) once per week for 6 weeks, 1-2 weeks following trans-urethral 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 x 10(6) cells/ml) and treated, or not, with lipopolysaccharide (LPS) (20 microgram/ml) for tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha) and interleukin-6 (IL-6) release. The levels of monokines were determined by a monokine-specific enzyme-linked immunosorbent assay. Our 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 TNF alpha and IL-1 alpha 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 x 10(6) cells/ml) from healthy subjects were pretreated, or not, with BCG (100 micrograms/ml) overnight and treated, or not, with LPS 20 microgram/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-1 alpha 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-1 alpha 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-1 alpha 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-1 alpha stimulated with LPS, but not BCG. The priming effect of BCG exerted on LPS-stimulated monocyte production of TNF alpha and IL-1 alpha 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 TNF alpha and IL-1 alpha, but not IL-6 in response to physiological secondary stimuli, or through the direct stimulation of BCG on IL-1 alpha or TNF alpha, which are directly involved in the killing of cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunomodulatory effects of recombinant BCG expressing MSP-1C ofPlasmodium falciparumon LPS- or LPS+IFN-γ-stimulated J774A.1 cells

“…[12][13][14][15][16][69][70][71][72] Similar to other results, the production of TNF-α and IL-1β by infected macrophages increased with LPS and LPS+IFN-γ. These results also consistent with several other studies showing that BCG stimulates the production of TNF-α and IL-1β by macrophages, [73][74][75] and the stimulation is enhanced in the presence of LPS 73 and further enhanced with the presence of LPS+IFN-γ. 76,77 We also demonstrated that phagocytosis of the BCG and rBCG strains not only reduced the viability of the macrophages but also resulted in a substantial reduction in replication of the mycobacteria.…”

House Dust Mite Allergens and the Induction of Monocyte Interleukin 1β Production That Triggers an IκBζ-Dependent Granulocyte Macrophage Colony-Stimulating Factor Release from Human Lung Epithelial Cells

“…It is therefore likely that the IL-1b that induces IkBz expression in the lung epithelial cells is released only by the monocytes present in the lungs when exposed to HDM. IL-1a is also known to be released by monocytes in response to LPS (45) and has been shown to regulate allergic responses to HDM in murine lung epithelial cells (12). Similar to IL-1b, we observed IL-1a release only from HDM-treated monocytes but not from macrophages, dendritic cells, or HBECs ( Figure 5A).…”

Low interleukin-1α messenger RNA levels predict decreased overall survival time of patients with urinary bladder carcinoma

“…After incubation with BCG, monocytes from treated patients show increased IL-1α and TNF-α production. It has been suggested that the beneficial immuno-therapeutic effects of BCG in bladder cancer patients are related to its capacity to prime macrophages to increase the release of IL-1α and TNF-α (Conti et al, 1994). uPA expression has been described as being stimulated by IL-1 (Leizer et al, 1987;Michel and Quertermous, 1989).…”