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The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.

Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, Briso EM, Charland C, Leonard WJ, Ciliberto G, Teuscher C, Haynes L, Rincon M - J. Exp. Med. (2009)

Bottom Line: IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro.Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production.IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.

ABSTRACT
Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4(+) T cells upon T cell receptor stimulation. IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

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Role of IL-21 and IL-6 in influenza virus infection. (A) Wild-type and IL-21−/− mice were infected i.n. with a sublethal dose (0.1 LD50) of active PR8 virus, and after 2 wk, influenza-specific IgG1 and IgG2c levels in serum were determined by ELISA. (B–D) Wild-type and IL-6−/− mice were infected i.n. with a sublethal dose (0.05 LD50) of active PR8 virus. Animals were monitored daily, and the time to death was recorded as the day after infection. Kaplan-Meier survival curves were generated using Prism 4.03 software (GraphPad Software, Inc.), and the log-rank test was used to determine the significance of differences between the strains (B). Weight was also measured daily in the surviving mice. The percentage of the initial weight is shown (C). Serum levels of virus-specific IgG1 were determined in the surviving mice (six out of six for wild-type mice and two out of six for IL-6−/− mice) 14 d after infection (D). Data represent groups of five (A) or six (B–D) mice from one experiment out of two performed. Error bars indicate SD.
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fig5: Role of IL-21 and IL-6 in influenza virus infection. (A) Wild-type and IL-21−/− mice were infected i.n. with a sublethal dose (0.1 LD50) of active PR8 virus, and after 2 wk, influenza-specific IgG1 and IgG2c levels in serum were determined by ELISA. (B–D) Wild-type and IL-6−/− mice were infected i.n. with a sublethal dose (0.05 LD50) of active PR8 virus. Animals were monitored daily, and the time to death was recorded as the day after infection. Kaplan-Meier survival curves were generated using Prism 4.03 software (GraphPad Software, Inc.), and the log-rank test was used to determine the significance of differences between the strains (B). Weight was also measured daily in the surviving mice. The percentage of the initial weight is shown (C). Serum levels of virus-specific IgG1 were determined in the surviving mice (six out of six for wild-type mice and two out of six for IL-6−/− mice) 14 d after infection (D). Data represent groups of five (A) or six (B–D) mice from one experiment out of two performed. Error bars indicate SD.

Mentions: Despite the established role of IL-21 in generation of plasma cells and antibody production, it remains unknown whether IL-21 plays a role in antibody response during influenza infection or any other viral infection. We therefore examined the contribution of endogenous IL-21 to the production of virus-specific antibodies in response to a sublethal dose (0.1 LD50) of the live PR8 influenza virus using wild-type and IL-21–deficient mice. 14 d after infection, influenza-specific antibody titers in serum were determined. Influenza-specific IgG1 and IgG2c levels were severely reduced in infected IL-21−/− mice compared with wild-type mice (Fig. 5 A). Thus, IL-21 plays a role in antibody response to influenza. We also examined the contribution of endogenous IL-6 to the antibody production against infection with PR8 infection using IL-6−/− mice. Interestingly, we found in repeated experiments that IL-6–deficient mice were highly susceptible to influenza virus infection, because a sublethal dose of live PR8 was sufficient to cause a relatively high rate of mortality in these mice but not in wild-type mice (Fig. 5 B), indicating that IL-6 is essential for protection against influenza virus. Unlike infected wild-type mice, infected IL-6−/− mice could not recover the weight loss caused by the acute viral infection (Fig. 5 C), suggesting that these mice could not clear or control the virus. Analysis of PR8-specific antibody production in the surviving IL-6−/− mice showed a reduction in virus antibody titers (Fig. 5 D). IL-6 is therefore a key cytokine for resolution of influenza virus infection.


The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells.

Dienz O, Eaton SM, Bond JP, Neveu W, Moquin D, Noubade R, Briso EM, Charland C, Leonard WJ, Ciliberto G, Teuscher C, Haynes L, Rincon M - J. Exp. Med. (2009)

Role of IL-21 and IL-6 in influenza virus infection. (A) Wild-type and IL-21−/− mice were infected i.n. with a sublethal dose (0.1 LD50) of active PR8 virus, and after 2 wk, influenza-specific IgG1 and IgG2c levels in serum were determined by ELISA. (B–D) Wild-type and IL-6−/− mice were infected i.n. with a sublethal dose (0.05 LD50) of active PR8 virus. Animals were monitored daily, and the time to death was recorded as the day after infection. Kaplan-Meier survival curves were generated using Prism 4.03 software (GraphPad Software, Inc.), and the log-rank test was used to determine the significance of differences between the strains (B). Weight was also measured daily in the surviving mice. The percentage of the initial weight is shown (C). Serum levels of virus-specific IgG1 were determined in the surviving mice (six out of six for wild-type mice and two out of six for IL-6−/− mice) 14 d after infection (D). Data represent groups of five (A) or six (B–D) mice from one experiment out of two performed. Error bars indicate SD.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2626667&req=5

fig5: Role of IL-21 and IL-6 in influenza virus infection. (A) Wild-type and IL-21−/− mice were infected i.n. with a sublethal dose (0.1 LD50) of active PR8 virus, and after 2 wk, influenza-specific IgG1 and IgG2c levels in serum were determined by ELISA. (B–D) Wild-type and IL-6−/− mice were infected i.n. with a sublethal dose (0.05 LD50) of active PR8 virus. Animals were monitored daily, and the time to death was recorded as the day after infection. Kaplan-Meier survival curves were generated using Prism 4.03 software (GraphPad Software, Inc.), and the log-rank test was used to determine the significance of differences between the strains (B). Weight was also measured daily in the surviving mice. The percentage of the initial weight is shown (C). Serum levels of virus-specific IgG1 were determined in the surviving mice (six out of six for wild-type mice and two out of six for IL-6−/− mice) 14 d after infection (D). Data represent groups of five (A) or six (B–D) mice from one experiment out of two performed. Error bars indicate SD.
Mentions: Despite the established role of IL-21 in generation of plasma cells and antibody production, it remains unknown whether IL-21 plays a role in antibody response during influenza infection or any other viral infection. We therefore examined the contribution of endogenous IL-21 to the production of virus-specific antibodies in response to a sublethal dose (0.1 LD50) of the live PR8 influenza virus using wild-type and IL-21–deficient mice. 14 d after infection, influenza-specific antibody titers in serum were determined. Influenza-specific IgG1 and IgG2c levels were severely reduced in infected IL-21−/− mice compared with wild-type mice (Fig. 5 A). Thus, IL-21 plays a role in antibody response to influenza. We also examined the contribution of endogenous IL-6 to the antibody production against infection with PR8 infection using IL-6−/− mice. Interestingly, we found in repeated experiments that IL-6–deficient mice were highly susceptible to influenza virus infection, because a sublethal dose of live PR8 was sufficient to cause a relatively high rate of mortality in these mice but not in wild-type mice (Fig. 5 B), indicating that IL-6 is essential for protection against influenza virus. Unlike infected wild-type mice, infected IL-6−/− mice could not recover the weight loss caused by the acute viral infection (Fig. 5 C), suggesting that these mice could not clear or control the virus. Analysis of PR8-specific antibody production in the surviving IL-6−/− mice showed a reduction in virus antibody titers (Fig. 5 D). IL-6 is therefore a key cytokine for resolution of influenza virus infection.

Bottom Line: IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro.Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production.IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405, USA.

ABSTRACT
Interleukin (IL) 6 is a proinflammtory cytokine produced by antigen-presenting cells and nonhematopoietic cells in response to external stimuli. It was initially identified as a B cell growth factor and inducer of plasma cell differentiation in vitro and plays an important role in antibody production and class switching in vivo. However, it is not clear whether IL-6 directly affects B cells or acts through other mechanisms. We show that IL-6 is sufficient and necessary to induce IL-21 production by naive and memory CD4(+) T cells upon T cell receptor stimulation. IL-21 production by CD4(+) T cells is required for IL-6 to promote B cell antibody production in vitro. Moreover, administration of IL-6 with inactive influenza virus enhances virus-specific antibody production, and importantly, this effect is dependent on IL-21. Thus, IL-6 promotes antibody production by promoting the B cell helper capabilities of CD4(+) T cells through increased IL-21 production. IL-6 could therefore be a potential coadjuvant to enhance humoral immunity.

Show MeSH
Related in: MedlinePlus