Enhanced Interleukin (IL)-13 Responses in Mice Lacking IL-13 Receptor α 2

Interleukin (IL)-13 has recently been shown to play important and unique roles in asthma, parasite immunity, and tumor recurrence. At least two distinct receptor components, IL-4 receptor (R)α and IL-13Rα1, mediate the diverse actions of IL-13. We have recently described an additional high affinity receptor for IL-13, IL-13Rα2, whose function in IL-13 signaling is unknown. To better appreciate the functional importance of IL-13Rα2, mice deficient in IL-13Rα2 were generated by gene targeting. Serum immunoglobulin E levels were increased in IL-13Rα2−/− mice despite the fact that serum IL-13 was absent and immune interferon γ production increased compared with wild-type mice. IL-13Rα2–deficient mice display increased bone marrow macrophage progenitor frequency and decreased tissue macrophage nitric oxide and IL-12 production in response to lipopolysaccharide. These results are consistent with a phenotype of enhanced IL-13 responsiveness and demonstrate a role for endogenous IL-13 and IL-13Rα2 in regulating immune responses in wild-type mice

Differential roles of ICAM-1 and VCAM-1 in leukocyte-endothelial cell interactions in skin and brain of MRL/faslpr mice

MRL/faslpr mice, which undergo a systemic autoimmune disease with similarities to systemic lupus erythematosus (SLE), display reduced pathology and prolonged survival if rendered deficient in ICAM-1. However, it remains unclear whether this is a result of the ability of ICAM-1 to promote the immune response or mediate leukocyte recruitment. Therefore, the aim of these studies was to compare the role of ICAM-1 in the elevated leukocyte-endothelial interactions, which affect MRL/faslpr mice. Intravital microscopy was used to compare leukocyte rolling and adhesion in postcapillary venules in the dermal and cerebral (pial) microcirculations of wild-type (ICAM+/+) and ICAM-1-deficient (ICAM-1−/−) MRL/faslpr mice. In the dermal microcirculation of 16-week MRL/faslpr mice, leukocyte adhesion was increased relative to nondiseased MRL+/+ mice. However, this increase was abolished in ICAM-1−/− MRL/faslpr mice. ICAM-1 deficiency was also associated with reduced dermal pathology. In contrast, in the pial microcirculation, the elevation in leukocyte adhesion observed in ICAM+/+ MRL/faslpr mice also occurred in ICAM-1−/− MRL/faslpr mice. VCAM-1 expression was detectable in both vascular beds, but higher levels were detected in the pial vasculature. Furthermore, VCAM-1 blockade significantly reduced leukocyte adhesion and rolling in the cerebral microcirculation of ICAM-1−/− MRL/faslpr mice. Therefore, ICAM-1 was critical for leukocyte adhesion in the skin but not the brain, where VCAM-1 assumed the major function. Given the ongoing development of anti-adhesion molecule therapies and their potential in inflammatory diseases such as SLE, these data indicate that implementation of these therapies in SLE should take into account the potential for tissue-specific functions of adhesion molecules