Interleukin-12 regulates the production of Bacille Calmette-Guerin- induced interferon-γ from human cells in a CD40-dependent manner

P. Méndez-Samperio, H. E. Ayala-Verdin, A. Trejo-Echeverria

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18 Citations (Scopus)

Abstract

Interferon (IFN)-γ is a cytokine which plays a critical role in the host defence against human tuberculosis infection. There is evidence that interleukin (IL)-12 can exert a potent effect in stimulating the production of IFN-γ and it is well known that a costimulatory signal provided by CD40 may enhance IL-12 production by monocytes/macrophages. However, it is unclear whether CD40-CD40L stimulation is able to regulate the production of mycobacterial-induced IFN-γ through an IL-12-dependent pathway. In this study, we investigated the capacity of the Bacille Calmette-Guerin (BCG) strain of Mycobacterium bovis to induce the production of interferon-γ through IL-12 and/or CD40 costimulation from human cells. Our data demonstrate that anti-IL-12 antibodies markedly reduced the levels of IFN-γ produced by the BCG-stimulated human cells, while exogenous recombinant (r)IL-12 up-regulated the production of IFN-γ. In addition, the stimulatory effect of IL-12 on BCG-induced IFN-γ secretion was specific, as it was significantly abolished in the presence of anti-IL-12 antibodies. We also observed that the presence of an anti-CD40L monoclonal antibody significantly inhibited the production of IL-12 and IFN-γ by human cells activated with BCG. In contrast, an isotype control antibody showed no effect on cytokine production. Furthermore, the presence of a trimeric soluble CD40L agonist (CD40T) in cultures increased the production of IL-12 and IFN-γ. Importantly, the stimulatory capacity of CD40T on BCG-induced IFN-γ secretion was blocked by a monoclonal antibody against IL-12, indicating that the effect of CD40T on T cells was mediated through IL-12. Together, these studies are the first to demonstrate that BCG-induced IFN-γ production by human cells appears to be mediated by IL-12 in a CD40-dependent manner and suggest that CD40-CD40L activation may be a critical mediator in regulating the immune response to stimulation with BCG.
Original languageAmerican English
Pages (from-to)61-67
Number of pages54
JournalScandinavian Journal of Immunology
StatePublished - 8 Jul 1999

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interferon
Interferons
interleukins
Interleukin-12
Cells
CD40 Ligand
antibodies
Antibodies
Monoclonal antibodies
secretions
stimulation
Monoclonal Antibodies
monocytes
T-cells
Cytokines
Macrophages
tuberculosis
macrophages
infectious diseases
Mycobacterium bovis

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title = "Interleukin-12 regulates the production of Bacille Calmette-Guerin- induced interferon-γ from human cells in a CD40-dependent manner",
abstract = "Interferon (IFN)-γ is a cytokine which plays a critical role in the host defence against human tuberculosis infection. There is evidence that interleukin (IL)-12 can exert a potent effect in stimulating the production of IFN-γ and it is well known that a costimulatory signal provided by CD40 may enhance IL-12 production by monocytes/macrophages. However, it is unclear whether CD40-CD40L stimulation is able to regulate the production of mycobacterial-induced IFN-γ through an IL-12-dependent pathway. In this study, we investigated the capacity of the Bacille Calmette-Guerin (BCG) strain of Mycobacterium bovis to induce the production of interferon-γ through IL-12 and/or CD40 costimulation from human cells. Our data demonstrate that anti-IL-12 antibodies markedly reduced the levels of IFN-γ produced by the BCG-stimulated human cells, while exogenous recombinant (r)IL-12 up-regulated the production of IFN-γ. In addition, the stimulatory effect of IL-12 on BCG-induced IFN-γ secretion was specific, as it was significantly abolished in the presence of anti-IL-12 antibodies. We also observed that the presence of an anti-CD40L monoclonal antibody significantly inhibited the production of IL-12 and IFN-γ by human cells activated with BCG. In contrast, an isotype control antibody showed no effect on cytokine production. Furthermore, the presence of a trimeric soluble CD40L agonist (CD40T) in cultures increased the production of IL-12 and IFN-γ. Importantly, the stimulatory capacity of CD40T on BCG-induced IFN-γ secretion was blocked by a monoclonal antibody against IL-12, indicating that the effect of CD40T on T cells was mediated through IL-12. Together, these studies are the first to demonstrate that BCG-induced IFN-γ production by human cells appears to be mediated by IL-12 in a CD40-dependent manner and suggest that CD40-CD40L activation may be a critical mediator in regulating the immune response to stimulation with BCG.",
author = "P. M{\'e}ndez-Samperio and Ayala-Verdin, {H. E.} and A. Trejo-Echeverria",
year = "1999",
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Interleukin-12 regulates the production of Bacille Calmette-Guerin- induced interferon-γ from human cells in a CD40-dependent manner. / Méndez-Samperio, P.; Ayala-Verdin, H. E.; Trejo-Echeverria, A.

In: Scandinavian Journal of Immunology, 08.07.1999, p. 61-67.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Interleukin-12 regulates the production of Bacille Calmette-Guerin- induced interferon-γ from human cells in a CD40-dependent manner

AU - Méndez-Samperio, P.

AU - Ayala-Verdin, H. E.

AU - Trejo-Echeverria, A.

PY - 1999/7/8

Y1 - 1999/7/8

N2 - Interferon (IFN)-γ is a cytokine which plays a critical role in the host defence against human tuberculosis infection. There is evidence that interleukin (IL)-12 can exert a potent effect in stimulating the production of IFN-γ and it is well known that a costimulatory signal provided by CD40 may enhance IL-12 production by monocytes/macrophages. However, it is unclear whether CD40-CD40L stimulation is able to regulate the production of mycobacterial-induced IFN-γ through an IL-12-dependent pathway. In this study, we investigated the capacity of the Bacille Calmette-Guerin (BCG) strain of Mycobacterium bovis to induce the production of interferon-γ through IL-12 and/or CD40 costimulation from human cells. Our data demonstrate that anti-IL-12 antibodies markedly reduced the levels of IFN-γ produced by the BCG-stimulated human cells, while exogenous recombinant (r)IL-12 up-regulated the production of IFN-γ. In addition, the stimulatory effect of IL-12 on BCG-induced IFN-γ secretion was specific, as it was significantly abolished in the presence of anti-IL-12 antibodies. We also observed that the presence of an anti-CD40L monoclonal antibody significantly inhibited the production of IL-12 and IFN-γ by human cells activated with BCG. In contrast, an isotype control antibody showed no effect on cytokine production. Furthermore, the presence of a trimeric soluble CD40L agonist (CD40T) in cultures increased the production of IL-12 and IFN-γ. Importantly, the stimulatory capacity of CD40T on BCG-induced IFN-γ secretion was blocked by a monoclonal antibody against IL-12, indicating that the effect of CD40T on T cells was mediated through IL-12. Together, these studies are the first to demonstrate that BCG-induced IFN-γ production by human cells appears to be mediated by IL-12 in a CD40-dependent manner and suggest that CD40-CD40L activation may be a critical mediator in regulating the immune response to stimulation with BCG.

AB - Interferon (IFN)-γ is a cytokine which plays a critical role in the host defence against human tuberculosis infection. There is evidence that interleukin (IL)-12 can exert a potent effect in stimulating the production of IFN-γ and it is well known that a costimulatory signal provided by CD40 may enhance IL-12 production by monocytes/macrophages. However, it is unclear whether CD40-CD40L stimulation is able to regulate the production of mycobacterial-induced IFN-γ through an IL-12-dependent pathway. In this study, we investigated the capacity of the Bacille Calmette-Guerin (BCG) strain of Mycobacterium bovis to induce the production of interferon-γ through IL-12 and/or CD40 costimulation from human cells. Our data demonstrate that anti-IL-12 antibodies markedly reduced the levels of IFN-γ produced by the BCG-stimulated human cells, while exogenous recombinant (r)IL-12 up-regulated the production of IFN-γ. In addition, the stimulatory effect of IL-12 on BCG-induced IFN-γ secretion was specific, as it was significantly abolished in the presence of anti-IL-12 antibodies. We also observed that the presence of an anti-CD40L monoclonal antibody significantly inhibited the production of IL-12 and IFN-γ by human cells activated with BCG. In contrast, an isotype control antibody showed no effect on cytokine production. Furthermore, the presence of a trimeric soluble CD40L agonist (CD40T) in cultures increased the production of IL-12 and IFN-γ. Importantly, the stimulatory capacity of CD40T on BCG-induced IFN-γ secretion was blocked by a monoclonal antibody against IL-12, indicating that the effect of CD40T on T cells was mediated through IL-12. Together, these studies are the first to demonstrate that BCG-induced IFN-γ production by human cells appears to be mediated by IL-12 in a CD40-dependent manner and suggest that CD40-CD40L activation may be a critical mediator in regulating the immune response to stimulation with BCG.

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