Delayed onset and reduced severity of collagen-induced arthritis in interleukin-6-deficient mice.
(33/2364)
OBJECTIVE: To investigate the roles of interleukin-6 (IL-6) in the pathogenesis of rheumatoid arthritis (RA) by studying its effect on murine collagen-induced arthritis (CIA). METHODS: IL-6-deficient (IL-6-/-) mice with a genetic background of susceptibility to CIA were generated by backcrossing them with DBA/1J mice for 8 generations. Clinical and immunologic features were compared between these mice and IL-6 wild-type (IL-6+/+) littermates with CIA. RESULTS: Serum IL-6 levels increased during the development of CIA in IL-6+/+ mice. Two prominent peaks were observed. The first was coincident with the onset of arthritis, and the second one was observed during exacerbation of the disease. The onset of arthritis in IL-6-/- mice was delayed for 2 weeks compared with that in IL-6+/+ mice, and the severity of arthritis, as indicated by the arthritis score, remained significantly lower in IL-6-/- mice during the entire followup period (14 weeks), although all IL-6-/- mice developed definite arthritis as did the IL-6+/+ mice. Histologic severity was also reduced in IL-6-/- mice. In addition, radiologic changes such as osteopenia and bone erosion were reduced significantly in these animals. Both humoral and cellular responses to type II collagen (CII) in IL-6-/- mice were reduced to about half those in IL-6+/+ mice. In addition, enhanced production of IL-4 and IL-10 in response to concanavalin A stimulation was observed in IL-6-/- mice. CONCLUSION: IL-6 plays an important role in the development of CIA, and both suppression of specific immune responses to CII and a tendency to a shift toward a Th2 cytokine profile might contribute in part to the attenuation of CIA in IL-6-/- mice. These findings suggest that blockade of IL-6 might be beneficial in the treatment of RA. (+info)
Intravenous tolerization with type II collagen induces interleukin-4-and interleukin-10-producing CD4+ T cells.
(34/2364)
Intravenous (i.v.) administration of type II collagen (CII) is an effective way to induce tolerance and suppress disease in the collagen-induced arthritis (CIA) model. In this study, we demonstrated that a single i.v. dose of CII (as low as 0.1 mg/mouse) completely prevented the development of CIA. This suppression was accompanied by decreases in levels of antibody specific for the immunogen, bovine CII and autoantigen, mouse CII. Splenocytes obtained from CII-tolerized mice and stimulated with CII in vitro produced predominantly the T helper 2 (Th2)-type cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10). In contrast, cells obtained from mice immunized with CII produced predominantly interferon-gamma (IFN-gamma). Two-colour flow cytometric analysis of cytokine expression and T-cell phenotype demonstrated that CD4+ cells and not CD8+ or gammadelta+ cells were the predominant regulatory cells producing IL-4 and IL-10. Transgenic mice bearing a T-cell receptor (TCR) specific for CII had a greater increase in the number of IL-4-secreting CD4+ cells, as well as a marked increase of IL-4 in culture supernatants. This cytokine was produced by transgene-bearing T cells. Elucidation of mechanisms for the induction of tolerance in mature T cells is an important line of study in autoimmune models because of the potential application for treating organ-specific autoimmune disease. (+info)
Acceleration and increased severity of collagen-induced arthritis in P-selectin mutant mice.
(35/2364)
P-selectin plays an important role in leukocyte adherence to microvascular endothelium and is expressed in synovial tissue from patients with rheumatoid arthritis (RA). However, the contribution of P-selectin to the initiation and chronicity of joint inflammation is not well understood. In these studies, collagen-induced arthritis (CIA) was induced in P-selectin mutant (-/-) mice to explore the role of P-selectin in the development of joint inflammation. Surprisingly, CIA onset was accelerated and severity was increased in P-selectin mutant mice, compared with wild-type mice (+/+). Increased levels of anti-type II collagen IgG were detected in both nonarthritic and arthritic P-selectin mutant mice from days 14-91. In addition, splenocytes isolated from immunized and nonimmunized P-selectin mutant mice produced significantly less IL-2 and IL-4, but significantly higher levels of IL-10 and IL-5 than splenocytes from wild-type mice. These observations show that P-selectin-mediated leukocyte rolling is not required for the development of murine CIA and that P-selectin expression exerts a controlling effect on the development of Ag-driven inflammatory joint disease, possibly by mediating the recruitment and/or trafficking of specific leukocyte subtypes into lymphoid tissue or inflammatory foci. (+info)
Identification of genes controlling collagen-induced arthritis in mice: striking homology with susceptibility loci previously identified in the rat.
(36/2364)
The susceptibility to collagen-induced arthritis in the highly susceptible DBA/1 mouse has earlier been shown to be partly controlled by the MHC class II gene Aq. To identify susceptibility loci outside of MHC, we have made crosses between DBA/1 and the less susceptible B10.Q strain, both expressing the MHC class II gene Aq. Analysis of 224 F2 intercross mice with 170 microsatellite markers in a genome-wide scan suggested 4 quantitative trait loci controlling arthritis susceptibility located on chromosomes 6, 7, 8, and 10. The locus on chromosome 6 (Cia6), which was associated with arthritis onset, yielded a logarithm of odds score of 4.7 in the F2 intercross experiment and was reproduced in serial backcross experiments. Surprisingly, the DBA/1 allele had a recessive effect leading to a delay in arthritis onset. The suggestive loci on chromosomes 7 and 10 were associated with arthritis severity rather than onset, and another suggestive locus on chromosome 8 was most closely associated with arthritis incidence. The loci on chromosomes 7, 8, and 10 all appeared to contain disease-promoting alleles derived from the DBA/1 strain. Interestingly, most of the identified loci were situated in chromosomal regions that are homologous to regions in the rat genome containing susceptibility genes for arthritis; the mouse Cia6 locus is homologous with the rat Cia3, Pia5, Pia2, and Aia3; the locus on chromosome 7 (Cia7) is homologous with the rat Cia2; and the locus on chromosome 10 (Cia8) is homologous with the rat Cia4. (+info)
WF14861, a new cathepsins B and L inhibitor produced by Colletotrichum sp. II. Biological properties.
(37/2364)
WF14861, 3-(N-(1-(N-(4-aminobutyl)-N-(3-aminopropyl)carbamoyl)-2-(4-hydroxyphenyl )ethyl)carbamoyl)oxirane-2-carboxylic acid, was obtained from the culture mycelium of Colletotrichum sp. as a novel cathepsins B and L inhibitor. WF14861 also showed inhibitory activities against bone derived crude protease and other cysteine proteases in vitro. The compound ameliorated the tissue damage and the bone destruction models of low-calcium-diet-fed mouse and adjuvant arthritis rat model. (+info)
Oral administration of lipopolysaccharide exacerbates collagen-induced arthritis in mice.
(38/2364)
We investigated whether oral administration of LPS exacerbated collagen-induced arthritis (CIA) in mice, which was an experimental model of autoimmune disease. CIA was induced by s.c. injection of type II collagen emulsified with CFA into the base of the tail (day 0) followed by a booster injection on day 21. To examine the ability of LPS to exacerbate CIA, varying doses of LPS were orally administered on day 50. The results showed that administration of LPS was followed by reactivation of CIA in a dose-related fashion. Histologically, on day 55 there were marked edema of synovium proliferated by day 50, new formation of fibrin, and intense infiltration of neutrophils accompanied with a large number of mononuclear cells. Severe destruction of cartilage and subchondral bone was also observed on day 70. The reactivation of CIA by oral administration of LPS was associated with increase in anti-type II collagen IgG and IgG2a Abs as well as varying kinds of cytokines including IL-12, IFN-gamma, IL-1beta, and TNF-alpha. Polymyxin B sulfate given either orally or i.v. suppressed the recurrence of CIA. Increased amounts of LPS were found in sera of mice given the endotoxin orally. LPS from Salmonella enteritidis, Salmonella typhimurium, and Klebsiella pneumoniae and its component, lipid A from Escherichia coli, also reactivated the disease. These findings suggest that LPS from intestinal bacteria may play a role in the exacerbation of autoimmune joint inflammation. (+info)
Enhanced autoimmune arthritis in IFN-gamma receptor-deficient mice is conditioned by mycobacteria in Freund's adjuvant and by increased expansion of Mac-1+ myeloid cells.
(39/2364)
Induction of experimental autoimmune diseases often relies on immunization with the organ-specific autoantigens in CFA, which contains heat-killed mycobacteria. In several of these models, including collagen-induced arthritis, endogenous IFN-gamma acts as a disease-limiting factor in the pathogenesis of the disease. Here we show that in collagen-induced arthritis the protective effect of IFN-gamma depends on the presence of mycobacteria in the adjuvant. Omission of mycobacteria inverts the role of endogenous IFN-gamma to a disease-promoting factor. Thus, the mycobacterial component of CFA opens a pathway by which endogenous IFN-gamma exerts a protective effect that supersedes its otherwise disease-promoting effect. Extramedullary hemopoiesis and expansion of the Mac-1+ cell population accompanied the accelerated and more severe disease course in the IFN-gamma receptor knockout mice immunized with CFA. Treatment of such mice with Abs against the myelopoietic cytokines IL-6 or IL-12 inhibited both disease development and the expansion of the Mac-1+ population. We postulate that mycobacteria in CFA stimulate the expansion of the Mac-1+ cell population by a hemopoietic process that is restrained by endogenous IFN-gamma. These results have important implications for the validity of animal models of autoimmunity to study the pathogenesis and to evaluate cytokine-based therapy of autoimmune diseases. (+info)
Dissociation between c-fos mRNA in the paraventricular nucleus and corticosterone secretion in rats with adjuvant-induced arthritis.
(40/2364)
Increased c-fos mRNA or fos immunoreactivity within the central nervous system has been used as a marker of neuronal activation. Acute stress and acute immune challenge result in an increase in c-fos mRNA in corticotrophin-releasing factor (CRF)-containing neurons in the paraventricular nucleus (PVN). It has often been implied that an increase in fos in the PVN can be equated to an increase in the activity of CRF itself, although there is some evidence to suggest these events are not linked. In the present study we have used the rat model of adjuvant-induced arthritis (AA), in which, despite the activation of the pituitary-adrenal system associated with inflammation, there is a paradoxical decrease in CRF mRNA and CRF peptide release. AA rats are unable to mount a hypothalamo-pituitary-adrenal (HPA) axis response to acute stress. They are, however, able to mount a response to acute immune stimulation, e.g. lipopolysaccharide injection. Despite the lack of HPA axis response to stress, there is an increase in c-fos mRNA to these challenges in AA. This suggests that the increase in c-fos mRNA in response to acute stress is not related to a subsequent increase in CRF mRNA in this model. We can conclude that under these conditions, c-fos mRNA is not a good marker of HPA axis activation and independent estimation of the involvement of CRF in the stimulation of the HPA axis should always be obtained. The AA model may prove useful for the comparison of the relationship between immediate early genes and heteronuclear RNAs in response to acute stress and immune stimuli with which to tease apart the molecular mechanisms underlying the control of releasing factor activation at the level of the PVN. (+info)