Exogenous cytokine modulation or neutralization of interleukin‐10 enhance survival in lipopolysaccharide‐hyporesponsive C3H/HeJ mice with <i>Klebsiella</i> infection

Wang, M.-J.; Jeng, Kee-Ching; Ping, Ling-In

doi:10.1046/j.1365-2567.1999.00838.x

Cited by 26 publications

(26 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since LPS is an important antigen in gram-negative bacteria and is capable of inducing a strong immune response, it was expected that the lack of functional TLR4 would render mice susceptible to gram-negative infections (5). Indeed, TLR4 seems to be important in host defense against some gram-negative bacteria, as shown by an impaired defense of TLR4 mutant mice during urinary tract infection with Escherichia coli (18) and intraperitoneal infection with Neisseria (51), Klebsiella (49), and Salmonella (4) species. However, host defense in TLR4 mutant mice with E. coli peritonitis was not impaired (17,20).…”

Section: Discussionmentioning

confidence: 99%

Role ofToll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia inMice

Branger

Knapp²,

Weijer³

et al. 2004

Infect Immun

224

209

View full text Add to dashboard Cite

To determine the role of Toll-like receptor 4 (TLR4) in the immune response to pneumonia, C3H/HeJ mice (which display a mutant nonfunctional TLR4) and C3H/HeN wild-type mice were intranasally infected with either Streptococcus pneumoniae (a common gram-positive respiratory pathogen) or Klebsiella pneumoniae (a common gram-negative respiratory pathogen). In cases of pneumococcal pneumonia, TLR4 mutant mice showed a reduced survival only after infection with low-level bacterial doses, which was associated with a higher bacterial burden in their lungs 48 h postinfection. In Klebsiella pneumonia, TLR4 mutant mice demonstrated a shortened survival after infection with either a low-or a high-level bacterial dose together with an enhanced bacterial outgrowth in their lungs. These data suggest that TLR4 contributes to a protective immune response in both pneumococcal and Klebsiella pneumonia and that its role is more important in respiratory tract infection caused by the latter (gram-negative) pathogen.

show abstract

Section: Discussionmentioning

confidence: 99%

Role ofToll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia inMice

Branger

Knapp²,

Weijer³

et al. 2004

Infect Immun

224

209

View full text Add to dashboard Cite

show abstract

“…These cytokines are known to affect the outcome in models of injury and infection. The anti-inflammatory effects of IL-10 have been found to be detrimental after injection of live bacteria (6,8,17,26,27). Manipulation of IL-10 in models of injury and infection has resulted in alterations of the outcome (Y. Kohda, H. Chiao, P. McLeory, L. Craig, and R. A.…”

Section: Discussionmentioning

confidence: 99%

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Jeyarajah

Kielar

Frantz

et al. 2003

Clin Vaccine Immunol

View full text Add to dashboard Cite

Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD 50 ) for E. coli injected into the bile duct was 50 CFU/animal; the LD 50 for E. coli injected into the portal vein was 5 ؋ 10 7 CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.Despite antibiotics and biliary drainage, either surgically or endoscopically, patients with ascending cholangitis have greater mortality and morbidity than patients with other appropriately treated intra-abdominal infections. In contrast to portal vein entry of bacteria into the liver, for example, after appendicitis or diverticulitis, entry via the biliary ducts has higher morbidity and mortality (4, 7). Indeed, small numbers of bacteria from the gastrointestinal tract may continually shower the liver via the portal vein without ill effect (11). This study reports a murine model that compares infection via the biliary and portal venous routes. This model reproduces the extraordinary mortality seen in patients after the former. Our model differs from others (9, 19). It focuses on early events within days of biliary infection, as opposed to late events after biliary obstruction has resulted in chronic liver injury.Our model suggests that the host response to infection via the bile duct is fundamentally different from the response to infection via the portal vein. We will show that one manifestation of this difference is the pattern of cytokines elicited by the infection. These cytokines affect the outcome in models of infection and injury and are supported by the literature. For example, levels of interleukin 6 (IL-6) in serum correlate with survival in critically ill patients; manipulat...

show abstract

“…Release of IL-10 in vivo has been shown in prior studies to be involved in host defense against a variety of other infectious agents, including Klebsiella pneumoniae (14,39), Listeria monocytogenes (7), Candida albicans (8,33), Trypanosoma cruzi (32), and Toxoplasma gondii (29). As a general rule, experimental depletion of IL-10 through antibody neutralization or usage of knockout mice leads to enhanced host responses and decreased susceptibility to infection, while elevation of IL-10 by administration of recombinant cytokine or usage of transgenic mice leads to decreased host responses and increased susceptibility to infection.…”

Section: Discussionmentioning

confidence: 99%

“…For example, IL-10 suppresses Th1 lymphocyte responses, activation of macrophages, and release of chemotactic factors for neutrophils. In bacterial pneumonia, neutralization of endogenous IL-10 enhances tissue inflammation and improves bacterial clearance (14,39).…”

mentioning

confidence: 99%

Local Delivery of the Viral Interleukin-10 Gene Suppresses Tissue Inflammation in MurinePneumocystis cariniiInfection

et al. 2002

View full text Add to dashboard Cite

The relationship between tissue inflammation and clearance of the opportunistic pathogen Pneumocystis carinii is poorly understood. We asked whether the anti-inflammatory cytokine interleukin-10 (IL-10) is released during the host response to infection with P. carinii and whether local delivery of the IL-10 gene could suppress tissue inflammatory responses without compromising clearance of infection. Control and CD4-depleted mice were inoculated with P. carinii, and at serial intervals after inoculation, lung tissue was assayed for IL-10 by enzyme-linked immunosorbent assay. We found that IL-10 was released in lung tissue in control mice and was present in higher concentrations in CD4-depleted mice with progressive infection. Control and CD4-depleted mice were then pretreated with 10 9 PFU of intratracheally administered adenoviral vector containing the viral IL-10 gene or the luciferase gene followed by inoculation with P. carinii. Pretreatment with viral IL-10 did not alter clearance of infection in control mice or severity of infection in CD4-depleted mice but did decrease tissue inflammation. We then asked whether gene transfer of viral IL-10 could decrease tissue inflammation during immune reconstitution. In these experiments, immunodeficient scid mice were inoculated with P. carinii and were heavily infected after 4 weeks. When these mice are immunologically reconstituted by intravenous administration of spleen cells from normal mice, a hyperinflammatory reaction developed in lung tissue, associated with high mortality. In comparison to control mice, mice treated with viral IL-10 prior to reconstitution showed significantly decreased lung wet weight, bronchoalveolar lavage fluid (BALF) lactate dehydrogenase, and BALF neutrophils. In contrast, infection intensity, as measured by PCR for P. carinii rRNA, was unchanged between the IL-10 and luciferase groups. Survival was also improved in the IL-10-treated mice. We conclude that release of IL-10 is part of the host response to infection with P. carinii and that gene therapy with viral IL-10 can lessen excessive tissue inflammation without altering pathogen clearance. In the setting of immune reconstitution and P. carinii pneumonia, pretreatment with the viral IL-10 gene decreases excessive tissue inflammation and improves survival. These results are relevant to acute respiratory failure after initiation of antibiotic treatment for human P. carinii pneumonia and to immune reconstitution syndromes in human immunodeficiency virus-positive patients started on highly active antiretroviral therapy.

show abstract

Exogenous cytokine modulation or neutralization of interleukin‐10 enhance survival in lipopolysaccharide‐hyporesponsive C3H/HeJ mice with Klebsiella infection

Cited by 26 publications

References 28 publications

Role ofToll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia inMice

Role ofToll-Like Receptor 4 in Gram-Positive and Gram-Negative Pneumonia inMice

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Local Delivery of the Viral Interleukin-10 Gene Suppresses Tissue Inflammation in MurinePneumocystis cariniiInfection

Contact Info

Product

Resources

About