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Immunoglobulin A1 protease, an exoenzyme of pathogenic Neisseriae, is a potent inducer of proinflammatory cytokines.

Lorenzen DR, Düx F, Wölk U, Tsirpouchtsidis A, Haas G, Meyer TF - J. Exp. Med. (1999)

Bottom Line: The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes.IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin.The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin, Germany.

ABSTRACT
A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-alpha and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.

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Comparison of cytokine production by PBMCs from different donors. PBMCs were cultured under low endotoxin conditions (<10 pg/ml as determined by the Limulus amebocyte lysate [LAL] assay). The indicated stimuli were added to the medium at the following concentrations: LPS, 30 ng/ml; PHA, 5 μg/ml; and IgA1 protease, 10 μg/ml. The cell-free supernatants were harvested after 18 h, pooled, and analyzed for the indicated cytokines by ELISA. Plots include data from n = 15 (for TNF-α [A] and IL-6 [C]) or n = 12 (for IL-1β [B] and IL-8 [D]) independent experiments. Boxes represent second and third quartiles; the lines within each box are the median values; the error bars represent 5 and 95% confidence. To compare cytokine levels in the different stimulation groups, the nonparametric Wilcoxon rank test was used. Results are considered as significantly different from values obtained with medium alone (*P < 0.05) and as significantly different from PHA (**P < 0.01).
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Figure 2: Comparison of cytokine production by PBMCs from different donors. PBMCs were cultured under low endotoxin conditions (<10 pg/ml as determined by the Limulus amebocyte lysate [LAL] assay). The indicated stimuli were added to the medium at the following concentrations: LPS, 30 ng/ml; PHA, 5 μg/ml; and IgA1 protease, 10 μg/ml. The cell-free supernatants were harvested after 18 h, pooled, and analyzed for the indicated cytokines by ELISA. Plots include data from n = 15 (for TNF-α [A] and IL-6 [C]) or n = 12 (for IL-1β [B] and IL-8 [D]) independent experiments. Boxes represent second and third quartiles; the lines within each box are the median values; the error bars represent 5 and 95% confidence. To compare cytokine levels in the different stimulation groups, the nonparametric Wilcoxon rank test was used. Results are considered as significantly different from values obtained with medium alone (*P < 0.05) and as significantly different from PHA (**P < 0.01).

Mentions: The cytokine release of PBMCs showed similar variations between different donors upon stimulation with either IgA1 protease, LPS, or PHA. As shown in Fig. 2 (A–D), the median levels of the proinflammatory cytokines detected in the presence of 10 μg/ml IgA1 protease were approximately similar to those found after LPS stimulation and sometimes even higher than those incubated with the lectin PHA.


Immunoglobulin A1 protease, an exoenzyme of pathogenic Neisseriae, is a potent inducer of proinflammatory cytokines.

Lorenzen DR, Düx F, Wölk U, Tsirpouchtsidis A, Haas G, Meyer TF - J. Exp. Med. (1999)

Comparison of cytokine production by PBMCs from different donors. PBMCs were cultured under low endotoxin conditions (<10 pg/ml as determined by the Limulus amebocyte lysate [LAL] assay). The indicated stimuli were added to the medium at the following concentrations: LPS, 30 ng/ml; PHA, 5 μg/ml; and IgA1 protease, 10 μg/ml. The cell-free supernatants were harvested after 18 h, pooled, and analyzed for the indicated cytokines by ELISA. Plots include data from n = 15 (for TNF-α [A] and IL-6 [C]) or n = 12 (for IL-1β [B] and IL-8 [D]) independent experiments. Boxes represent second and third quartiles; the lines within each box are the median values; the error bars represent 5 and 95% confidence. To compare cytokine levels in the different stimulation groups, the nonparametric Wilcoxon rank test was used. Results are considered as significantly different from values obtained with medium alone (*P < 0.05) and as significantly different from PHA (**P < 0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195656&req=5

Figure 2: Comparison of cytokine production by PBMCs from different donors. PBMCs were cultured under low endotoxin conditions (<10 pg/ml as determined by the Limulus amebocyte lysate [LAL] assay). The indicated stimuli were added to the medium at the following concentrations: LPS, 30 ng/ml; PHA, 5 μg/ml; and IgA1 protease, 10 μg/ml. The cell-free supernatants were harvested after 18 h, pooled, and analyzed for the indicated cytokines by ELISA. Plots include data from n = 15 (for TNF-α [A] and IL-6 [C]) or n = 12 (for IL-1β [B] and IL-8 [D]) independent experiments. Boxes represent second and third quartiles; the lines within each box are the median values; the error bars represent 5 and 95% confidence. To compare cytokine levels in the different stimulation groups, the nonparametric Wilcoxon rank test was used. Results are considered as significantly different from values obtained with medium alone (*P < 0.05) and as significantly different from PHA (**P < 0.01).
Mentions: The cytokine release of PBMCs showed similar variations between different donors upon stimulation with either IgA1 protease, LPS, or PHA. As shown in Fig. 2 (A–D), the median levels of the proinflammatory cytokines detected in the presence of 10 μg/ml IgA1 protease were approximately similar to those found after LPS stimulation and sometimes even higher than those incubated with the lectin PHA.

Bottom Line: The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes.IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin.The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction.

View Article: PubMed Central - PubMed

Affiliation: Max-Planck-Institut für Infektionsbiologie, Abteilung Molekulare Biologie, 10117 Berlin, Germany.

ABSTRACT
A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-alpha and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.

Show MeSH
Related in: MedlinePlus