IL-4 Deficiency Decreases Mortality but Increases Severity of Arthritis in Experimental Group B Streptococcus Infection

IL-4 is an anti-inflammatory cytokine that inhibits the onset and severity in different experimental arthritis models. Group B streptococci (GBS) have been recognized as an ever-growing cause of serious invasive infections in nonpregnant adults. Septic arthritis is a clinical manifestation of GBS infection. To investigate the role of IL-4 in experimental GBS infection, IL-4 deficient or competent mice were inoculated with 1 × 107 GBS/mouse. Mortality, appearance of arthritis, GBS growth in the organs, and local and systemic cytokine and chemokine production were examined. IL-4−/− mice showed lower mortality rates but increased severity of arthritis and exhibited a lower microbial load in blood, kidneys, and joints than wt mice. Increased local levels of IL-1 β, IL-6, TNF-α, MIP-1α, and MIP-2 accompanied the more severe arthritis in IL-4−/− mice. Our results suggest a detrimental role of IL-4 in GBS sepsis, whereas it plays a beneficial effect on GBS-induced arthritis

Role of macrophages in experimental group B streptococcal arthritis.

Septic arthritis is a clinical manifestation of group B Streptococcus (GBS) infection in both neonates and adults. Because macrophages are known to participate in tissue injury, the role of this cell population in GBS-induced arthritis was investigated. Mice were rendered monocytopenic by administration of etoposide, a drug that selectively depletes the monocyte/macrophage population and then injected with GBS (1 x 10(7) colony-forming units per mouse). Appearance of arthritis, mortality, GBS growth in the organs, and local and systemic cytokine production were examined. Etoposide-treated mice had a significantly less severe arthritis than control animals. Histopathological analysis of the joints confirmed clinical observations. Decreased joint levels of the proinflammatory cytokines interleukin 1 (IL-1) beta and IL-6 accompanied the less severe development of arthritis in monocytopenic mice. In contrast, mortality was increased in the etoposide-treated mice compared with controls. Monocytopenic mice exhibited elevated bacterial load in the blood and kidneys at all time points examined. These results indicate that lack of macrophages leads to less severe joint lesions, but also results in impaired clearance of bacteria, and consequent enhancement of mortality rates

IL-4 deficiency decreases mortality but increases severity of arthritis in experimental group B Streptococcus infection. Mediators Inflamm 2009; 2009:394021. doi

Recommended by Vera L. Petricevich IL-4 is an anti-inflammatory cytokine that inhibits the onset and severity in different experimental arthritis models. Group B streptococci (GBS) have been recognized as an ever-growing cause of serious invasive infections in nonpregnant adults. Septic arthritis is a clinical manifestation of GBS infection. To investigate the role of IL-4 in experimental GBS infection, IL-4 deficient or competent mice were inoculated with 1 × 10 7 GBS/mouse. Mortality, appearance of arthritis, GBS growth in the organs, and local and systemic cytokine and chemokine production were examined. IL-4-/-mice showed lower mortality rates but increased severity of arthritis and exhibited a lower microbial load in blood, kidneys, and joints than wt mice. Increased local levels of IL-1 β, IL-6, TNF-α, MIP-1α, and MIP-2 accompanied the more severe arthritis in IL-4-/-mice. Our results suggest a detrimental role of IL-4 in GBS sepsis, whereas it plays a beneficial effect on GBS-induced arthritis

Inhibition of Nitric Oxide Synthase Exacerbates Group B Streptococcus Sepsis and Arthritis in Mice

The role of nitric oxide in group B Streptococcus (GBS) infection was evaluated by inhibiting its production with aminoguanidine (AG). AG-treated mice displayed higher mortality rates and more frequent and severe arthritis than controls. Worsening of arthritis correlated with a higher number of GBS cells in the joints and local interleukin-1β production

Toll-Like Receptor 2 Deficiency Is Associated with Enhanced Severity of Group B Streptococcal Disease ▿

Group B streptococcus (GBS) has been recognized as an ever-growing cause of serious invasive infections in nonpregnant adults, in particular, in association with severe underlying diseases. The most common manifestations include primary bacteremia, urinary tract infections, pneumonia, meningitis, peritonitis, and osteoarticular infections. Toll-like receptor-2 (TLR2) mediates host responses to gram-positive bacteria. TLR2 function was investigated in murine GBS-induced sepsis and arthritis in wild-type (wt) and TLR2-deficient (TLR2−/−) mice. Mice were infected with different doses of GBS (107, 5 × 106, or 106 CFU per mouse). Mortality, appearance of arthritis, GBS growth in the organs, and local and systemic cytokine and chemokine production were examined. TLR2−/− mice showed earlier and higher mortality rates and increased incidence and severity of arthritis than wt mice at all the infecting doses employed. Histopathological analysis of the joints confirmed clinical observations. TLR2−/− mice exhibited a higher microbial load in blood, kidneys, and joints than wt animals. In vitro experiments performed with peritoneal polymorphonuclear cells and macrophages showed a significantly lower bactericidal ability of cells from TLR2−/− mice. Increased systemic and local levels of interleukin-1β (IL-1β), IL-6, tumor necrosis factor alpha, macrophage inflammatory protein-1α (MIP-1α), and MIP-2 accompanied the more severe development of sepsis and arthritis in TLR2−/− mice. In conclusion, the lack of TLR2 was associated with an impaired host resistance to GBS infection, likely due to a diminished bacterial clearing and a consequent enhanced inflammatory response

Glucuronoxylomannan, the Major Capsular Polysaccharide of Cryptococcus neoformans, Inhibits the Progression of Group B Streptococcal Arthritis

Glucuronoxylomannan (GXM), the principal constituent of the Cryptococcus neoformans capsule, modulates the inflammatory response of human monocytes in vitro. Here we examine the efficacy of GXM as a novel anti-inflammatory compound for use against experimental septic arthritis. Arthritis was induced in mice by the intravenous injection of 8 × 10(6) CFU of type IV group B streptococcus (GBS). GXM was administered intravenously in different doses (50, 100, or 200 μg/mouse) 1 day before and 1 day after bacterial inoculation. GXM treatment markedly decreased the incidence and severity of articular lesions. Histological findings showed limited periarticular inflammation in the joints of GXM-treated mice, confirming the clinical observations. The amelioration of arthritis was associated with a significant reduction in the local production of interleukin-6 (IL-6), IL-1β, macrophage inflammatory protein 1α (MIP-1α), and MIP-2 and an increase in systemic IL-10 levels. Moreover, peritoneal macrophages derived from GXM-treated mice and stimulated in vitro with heat-inactivated GBS showed a similar pattern of cytokine production. The present study provides evidence for the modulation of the inflammatory response by GXM in vivo and suggests a potential therapeutic use for this compound in pathologies involving inflammatory processes

Regulatory Role of Interleukin-10 in Experimental Group B Streptococcal Arthritis

Intravenous inoculation of CD-1 mice with 10(7) CFU of type IV group B Streptococcus (GBS) results in a high incidence of diffuse septic arthritis , associated with high levels of systemic and local production of interleukin-1β (IL-1β) and IL-6. In this study, the role of the anti-inflammatory cytokine IL-10 in the evolution of GBS systemic infection and arthritis was evaluated. IL-10 production was evident in sera and joints of GBS-infected mice. Neutralization of endogenous IL-10 by administration of anti-IL-10 antibodies (1 mg/mouse) at the time of infection resulted in worsening of articular lesions and 60% mortality associated with early sustained production of IL-6, IL-1β, and tumor necrosis factor alpha (TNF-α). The effect of IL-10 supplementation was assessed by administering IL-10 (100, 200, or 400 ng/mouse) once a day for 5 days, starting 1 h after infection. Treatment with IL-10 had a beneficial effect on GBS arthritis, and there was a clear-cut dose dependence. The decrease in pathology was associated with a significant reduction in IL-6, IL-1β, and TNF-α production. Histological findings showed limited periarticular inflammation and a few-cell influx in the articular cavity of IL-10-treated mice, confirming clinical observations. In conclusion, this study provides further information concerning the role of IL-10 in regulating the immune response and inflammation and calls attention to the potential therapeutic use of IL-10 in GBS arthritis