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. 1999 Apr;67(4):1901-9.
doi: 10.1128/IAI.67.4.1901-1909.1999.

Effects of interleukin-1 receptor antagonist overexpression on infection by Listeria monocytogenes

V M Irikura  1 , E Hirsch, D Hirsh
Affiliations

Effects of interleukin-1 receptor antagonist overexpression on infection by Listeria monocytogenes

V M Irikura et al. Infect Immun. 1999 Apr.

Abstract

Interleukin-1 receptor antagonist (IL-1ra) is a naturally occurring cytokine whose only known function is the inhibition of interleukin-1 (IL-1). Using a reverse genetic approach in mice, we previously showed that increasing IL-1ra gene dosage leads to reduced survival of a primary listerial infection. In this study, we characterize further the role of endogenously produced IL-1ra and, by inference, IL-1 in murine listeriosis. IL-1ra overexpression inhibits, but does not eliminate, primary immune responses, reducing survival and increasing bacterial loads in the target organs. We demonstrate that IL-1ra functions in the innate immune response to regulate the peak leukocyte levels in the blood, the accumulation of leukocytes at sites of infection, and the activation of macrophages during a primary infection. Reduced macrophage class II major histocompatibility complex expression was observed despite increased gamma interferon (IFN-gamma) levels, suggesting that IL-1 activity is essential along with IFN-gamma for macrophage activation in vivo. We also show that IL-1ra plays a more limited role during secondary listeriosis, blunting the strength of the delayed-type hypersensitivity response to listerial antigen while not significantly altering cellular immunity to a second infectious challenge. When these results are compared to those for other mutant mice, IL-1ra appears to be unique among the cytokines studied to date in its regulation of leukocyte migration during primary listeriosis.

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Figures

FIG. 1
FIG. 1
Bacterial titers throughout the course of a primary infection. Data from a representative experiment of four is shown. Wild-type (WT) and IL-1ra-overexpressing (T20) mice were infected i.v. with 1,150 CFU of Listeria, and the bacterial burdens in the organs from individual mice were determined on various days postinfection. The titers present in the livers and spleens are shown as CFU per gram of organ to correct for differences in sample size. The mean values are indicated by horizontal lines. Note that the scales differ in the various panels of the figure. The differences in bacterial titer were significant (P ≤ 0.05 [Mann-Whitney U test]) only on days 4 and 12 postinfection, although the trend toward higher mean titers in IL-1ra overexpressors is consistently observed at other time points.
FIG. 2
FIG. 2
Peritoneal exudate cells. The total number of PECs is shown for both wild-type (WT) and IL-1ra-overexpressing (T20) mice during a primary listerial infection. All mice were infected intraperitoneally on day 0, and individual mice were sacrificed on each of four subsequent days. Sham-infected mice had no alterations in WBC numbers compared to uninfected controls (data not shown). The day 0 data shown here is derived from uninfected mice. The data at each time point represents the mean ± the SEM of three to five individual mice. For clarity, positive error bars are shown for wild-type mice and negative error bars are shown for the IL-1ra-overexpressing mice; where not shown, the error bar is smaller than the size of the data point itself. Data from a representative experiment of three is shown; only those differences which were statistically significant in all experiments are indicated by an asterisk (P ≤ 0.05).
FIG. 3
FIG. 3
Histology of the livers of Listeria-infected mice. Representative sections of infectious foci and surrounding hepatocytic parenchyma from IL-1ra overexpressors and wild-type controls on day 2 postinfection are shown (original magnification, ×400). Hematoxylin-eosin (H & E) staining shows coagulative necrosis of infected hepatocytes and a marked reduction in WBC accumulation at the infectious focus of mice overexpressing IL-1ra (B) compared to that seen in wild-type mice (A). Gram staining of serial sections shows the localization of bacteria within both phagosomes (arrows) and necrotizing hepatocytes (arrowheads). While most of the bacteria are efficiently contained within the granuloma of wild-type mice (C), large numbers of bacteria appear to be free in the cytoplasm of infected hepatocytes within and beyond the initial infectious lesion in the IL-1ra overexpressors (D).
FIG. 4
FIG. 4
Activation of peritoneal macrophages during listeriosis. The percentage (A) and total numbers (B) of peritoneal macrophages expressing class II MHC, as judged by antibody staining for I-A antigen, are shown for wild type (WT) and IL-1ra overexpressors (T20). The data at each time point represents the mean ± SEM of three to five individual mice. Day 0 data in the experiment shown is derived from uninfected mice. Data from a representative experiment of three is shown; only those differences which were statistically significant in all experiments are indicated by an asterisk (P ≤ 0.05).
FIG. 5
FIG. 5
Distribution of cells expressing IL-1ra mRNA in the livers of infected mice detected by in situ hybridization. Shown are representative serial sections from the liver of a wild-type mouse 3 days after infection with a sublethal dose of Listeria (original magnification, ×160). (A) In situ hybridization with the antisense probe shows very strong IL-1ra mRNA expression in the WBC throughout the hepatic granuloma. A weaker but clear signal is also detected in the hepatocytes surrounding the infectious focus. (B) In situ hybridization with the negative control sense probe shows the specificity of the IL-1ra signal. (C) Hematoxylin-eosin-stained near-serial section shows the infectious lesion marked by a strong WBC influx as well as the surrounding apparently uninfected hepatic parenchyma.
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