[Show abstract][Hide abstract] ABSTRACT: C17 was first described about ten years ago as a gene expressed in CD34+ cells. A more recent study has suggested a role for C17 in chondrogenesis and development of cartilage. However, based on sequence analysis, we believe that C17 has homology to IL-2 and hence we present the hypothesis that C17 is a cytokine possessing immune-regulatory properties. We provide evidence that C17 is a secreted protein preferentially expressed in chondrocytes, hence in cartilage-rich tissues. Systemic expression of C17 in vivo reduces disease in a collagen antibody-induced arthritis model in mice (CAIA). Joint protection is evident by delayed disease onset, minimal edema, bone protection and absence of diverse histological features of disease. Expression of genes typically associated with acute joint inflammation and erosion of cartilage or bone is blunted in the presence of C17. Consistent with the observed reduction in bone erosion, we demonstrate reduced levels of RANKL in the paws and sera of mice over-expressing C17. Administration of C17 at the peak of disease, however, had no effect on disease progression, indicating that C17's immune-regulatory activity must be most prominent prior to or at the onset of severe joint inflammation. Based on this data we propose C17 as a cytokine that s contributes to immune homeostasis systemically or in a tissue-specific manner in the joint.
[Show abstract][Hide abstract] ABSTRACT: IL-33 is an IL-1-related cytokine which has been implicated in Th2-associated biology and allergic diseases in humans and mice. IL-33 stimulates Th2 cells, mast cells, eosinophils, basophils, iNKT cells and circulating CD34+ stem cells to proliferate and produce pro-allergic cytokines such as IL-5 and IL-13. IL-33 mediates its cytokine effects
through a receptor consisting of ST2 and IL-1RAcP. Whereas IL-1RAcP is ubiquitously expressed, ST2 expression is cell-type
restricted and determines responsiveness to IL-33. Studies employing ST2-deficient mice have reported variable results on
the role of this receptor, and consequently IL-33, with regards to allergic lung inflammation. In this study, we demonstrate
that IL-33 is important for allergic lung inflammation. Intra-nasal administration of IL-33 triggered an immediate allergic
response in the airways, and more importantly, we show that endogenous IL-33 contributes to airway inflammation and peripheral
antigen-specific responses in ovalbumin-induced acute allergic lung inflammation using IL-33-deficient mice. Our results suggest
that IL-33 is sufficient and required for severe allergic inflammation in the lung and support the concept of IL-33 as a therapeutic
target in allergic lung inflammation.
Preview · Article · Mar 2011 · International Immunology
[Show abstract][Hide abstract] ABSTRACT: IL-33 is constitutively expressed in epithelial barrier tissues, such as skin. Although increased expression of IL-33/IL-33R has been correlated with fibrotic disorders, such as scleroderma and progressive systemic sclerosis, the direct consequences of IL-33 release in skin has not been reported. To determine the effects of dysregulated IL-33 signaling in skin, we administered IL-33 s.c. and monitored its effects at the injection site. Administration of IL-33 resulted in IL-33R-dependent accumulation of eosinophils, CD3(+) lymphocytes, F4/80(+) mononuclear cells, increased expression of IL-13 mRNA, and the development of cutaneous fibrosis. Consistent with extensive cutaneous tissue remodeling, IL-33 resulted in significant modulation of a number of extracellular matrix-associated genes, including collagen VI, collagen III, and tissue inhibitor of metalloproteases-1. We establish that IL-33-induced fibrosis requires IL-13 using IL-13 knockout mice and eosinophils using Delta dblGATA mice. We show that bone marrow-derived eosinophils secrete IL-13 in response to IL-33 stimulation, suggesting that eosinophil-derived IL-13 may promote IL-33-induced cutaneous fibrosis. Collectively, our results identify IL-33 as a previously unrecognized profibrotic mediator in skin and highlight the cellular and molecular pathways by which this pathology develops.
Full-text · Article · Feb 2010 · The Journal of Immunology