The involvement of proinflammatory cytokines interleukin (IL)-1 and tumor necrosis factor (TNF) in crescentic glomerulonephritis (GN) is well established. Recently the requirement of intrinsic renal cell participation via their production of TNF in crescentic GN was demonstrated. The current studies address the relative contributions of leukocyte and intrinsic renal cell-derived IL-1beta in the induction of TNF production and glomerular injury by studying bone marrow chimeric mice. Leukocyte-derived IL-1beta was critical in the development of crescentic renal injury because IL-1beta(-/-)-->WT (absent leukocyte IL-1beta) chimeric mice had significantly attenuated TNF expression and were protected from the development of crescentic GN. In contrast, WT-->IL-1beta(-/-) chimeric mice (intact leukocyte but absent renal IL-1beta) developed similar TNF expression and crescentic GN to wild-type mice. To determine the cellular target for IL-1 in this model, IL-RI chimeric mice were studied. IL-1RI(-/-)-->WT chimeric (absent leukocyte IL-1RI expression) mice showed no attenuation of crescentic GN, whereas in the absence of renal IL-1RI (WT-->IL-1RI(-/-) chimeras), glomerular TNF expression and the development of crescentic GN were significantly decreased. These studies demonstrate that leukocytes are the major cellular source of IL-1beta, and that IL-1beta acts principally via the IL-1RI on intrinsic renal cells to induce TNF expression and crescentic glomerular injury.

Abstract. Interleukin-1 (IL-1) is a pleiotropic proinflammatory cytokine with two distinct isoforms (IL-1␣ and IL-1␤) that signal through the same IL-1 type I receptor (IL-1RI). Contributions of IL-1␤ have been demonstrated in human and experimental proliferative glomerulonephritis (GN), but the involvement of IL-1␣ has received little attention. To determine the combined contribution of IL-1␣ and IL-1␤ and to dissect the specific contribution of IL-1␤, the development of antiglomerular basement membrane globulin-induced crescentic GN was studied in mice genetically deficient in either the IL-1 receptor type I (IL-1RIϪ/Ϫ), which are unresponsive to both IL-1␣ and IL-1␤, or IL-1␤ alone (IL-1␤Ϫ/Ϫ). IL-1␤Ϫ/Ϫ mice showed significant reductions in crescent formation and glomerular T cell and macrophage recruitment compared with strain matched controls (WT). No additional reductions of these indices of injury were observed in IL-1RIϪ/Ϫ mice. However, IL-1RIϪ/Ϫ mice showed greater functional renal protection with significantly less proteinuria and reduced serum creatinine compared with IL-1␤Ϫ/Ϫ mice, suggesting a significant contribution of IL-1␣ to these parameters of injury. IL-1RIϪ/Ϫ mice had lower serum titers of antibody to the nephritogenic antigen (sheep globulin) and reduced glomerular deposition of complement compared with either IL-1␤Ϫ/Ϫ or WT mice. This suggests that in the absence of responses to both IL-1␣ and IL-1␤, attenuation of humoral mediators provides additional functional protection from renal injury that is not seen in the absence of IL-1␤ alone. These studies indicate that IL-1␤ but not IL-1␣ contributes to crescent formation and inflammatory cell recruitment, whereas IL-1␣ but not IL-1␤ contributes to humoral mechanisms of glomerular injury.

Using IL-1/IL-1Ra knockout BALB/c mice, we showed that 3-methylcholatrene (3-MCA)-induced carcinogenesis is dependent on IL-1β-induced inflammatory responses. Patterns of local inflammation and tumorigenicity were similar in wild-type (WT) and IL-1α−/− mice, while in IL-1β−/− mice, tumorigenicity was attenuated and in IL-1Ra−/− mice accentuated. 3-MCA-induced fibrosarcoma cell lines from WT mice developed into progressive tumors in WT mice, while surprisingly, lines from IL-1α−/− mice formed tumors only in immunocompromized mice. 3-MCA-induced fibrosarcoma cell lines from IL-1α−/− mice, compared with lines from WT mice, manifested higher expression levels of “global” surface molecules related to Ag presentation and interactions with immune surveillance cells (MHC class I, B7.1, B7.2, L-selectin, and NKG2D ligands) and were eradicated mainly by CD4+- and CD8+-dependent T cell responses. Concomitantly, at the injection site of 3-MCA-induced fibrosarcoma cells derived from IL-1α−/− mice, a leukocyte infiltrate, subsequently replaced by a scar-like tissue, was observed. Immune aberrations in NK cell maturation, antitumor specific immunity and killing capacity of effector cells were observed in IL-1α−/− mice, in contrast to WT mice. Thus, we demonstrate in this study the significance of host-derived IL-1α in cancer immunoediting, by affecting innate and specific immunosurveillance mechanisms. Overall, the results presented in this study, together with our previous studies, attest to differential involvement of IL-1α and IL-1β in tumorigenesis; host-derived IL-1β mainly controls inflammation, while concomitantly, IL-1α controls immunosurveillance of the arising malignant cells. Elucidation of the involvement of the IL-1 molecules in the malignant process will hopefully lead to the development of novel approaches for chemoprevention and immunotherapy.

Background IL-21 is secreted by activated T cells and modulates immune cell functions with both proinflammatory and anti-inflammatory effects. IL-21 receptor (IL-21R), homologous to IL-2Rβ and IL-4Rα, associates with the gamma common chain upon ligand binding. It was recently described that IL-21R is overexpressed in the inflamed synovial membrane and on leucocytes of rheumatoid arthritis patients. Objective Previously we have shown that blockade of the IL-21 pathway with soluble IL-21R-Fc resulted in a reduction of clinical signs of arthritis in rodent models. To understand potential mechanisms of IL-21 regulation in arthritis, we analyzed serum immunoglobulin levels, and cytokine expression in the paws, serum, and collagen-restimulated splenocytes, in response to IL-21 pathway blockade. Methods Arthritis was induced in DBA/1 male mice with bovine type II collagen. Animals were treated with either soluble mIL-21R-Fc, which neutralizes murine IL-21 bioactivity, with TNFRII-Fc or with control IgG. Spleens from each group of treated mice were cultured in vitro with collagen and assayed for cytokine secretion. Cytokines and anticollagen-specific IgG levels were also measured in the serum by ELISA. Cytokine mRNA levels in the paws were evaluated by quantitative PCR analysis. Results Treatment of mice with IL-21R-Fc or TNFRII-Fc reduced clinical and histological signs of collagen-induced arthritis. IL-6 mRNA in paws and serum IL-6 levels were decreased after IL-21R-Fc treatment. IFNγ mRNA was increased in paws of IL-21R-Fctreated mice. Collagen-specific spleen cell responses from IL-21R-Fc-treated mice exhibited increased IFNγ and IL-2, and reduced IL-6 and IL-17 levels. Serum levels of total IgG 1 were also reduced in response to IL-21R-Fc treatment. Conclusion These data demonstrate a role for IL-21 in the modulation of collagen-specific T-cell responses and the pathology of arthritis, supporting a rationale for blockade of the IL-21 pathway in rheumatoid arthritis. Background TNFα is a key cytokine in rheumatoid arthritis (RA) physiopathology. We recently demonstrated that a new cationic liposome formulation allowed intravenous delivery of a small interfering RNA (siRNA) targeting TNFα and efficiently restoring the immunological balance in an experiment model of RA. Since 30% of patients do not respond to anti-TNF biotherapies, however, there is a need to develop alternative therapeutic approaches. Objective Strong association of other proinflammatory cytokines with the pathogenesis of RA prompted us to investigate which cytokine other than TNFα could be targeted for therapeutic benefit using RNA interference. Methods Two siRNA sequences were designed for IL-1β, IL-6 and IL-18 proinflammatory cytokines, and their efficacy and specificity were validated in vitro on J774.1 mouse macrophage cells, measuring both mRNA and protein levels following a lipopolysaccharide challenge. For in vivo administration, siRNAs were formulated as lipoplexes with the RPR209120/DOPE liposome and a carrier DNA, and were injected intrav...

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