ABSTRACT
The development of type II collagen-induced arthritis (CIA) in DBA/1 mice is readily accelerated by treatments with interleukin-1 beta (IL-1 beta). In an attempt to further characterize this IL-1 beta-mediated enhancement of CIA, we first examined the effects of IL-1 beta treatments in other "CIA-susceptible" strains and "CIA-resistant" mice. It was observed that treatments with IL-1 beta also enhanced the onset of arthritis in two B10 recombinant CIA-susceptible strains, B10.T (6R) and B10.DA, and in the SJL mice which develop CIA with a relatively low and variable incidence. On the other hand, IL-1 beta failed to augment the expression of arthritic disease in several CIA-resistant strains. We also investigated the potentiating effects of IL-1 beta in mice that were depleted of L3T4+ T cells. It was found that the ability of IL-1 beta to accelerate the development of CIA was significantly reduced in DBA/1 mice pretreated with the monoclonal anti-L3T4 antibody. In further studies, we demonstrated that the induction of CIA upon transfer with collagen-primed spleen cells was also augmented by IL-1 beta, and this enhancing effect by IL-1 beta on the adoptive transfer of CIA was associated with a significant increase in the levels of serum anti-collagen antibodies. Moreover, IL-1 beta treatments did not potentiate the induction of CIA in mice that were transferred with either collagen-immune splenic cells that were depleted of L3T4+ T cells or only T cells obtained from collagen-immunized animals. However, IL-1 beta enhanced the development of arthritis in animals that had been transferred with two subpopulations of collagen-immune cells: (i) enriched T cells and (ii) splenic cells that were depleted of L3T4+ T cells. Thus, IL-1 beta potentiated the inflammatory responses in animals that were genetically predisposed to developing arthritis. In contrast, IL-1 beta was incapable of accelerating the development of arthritis in various mouse strains that were genetically resistant to CIA. The administration of IL-1 beta also failed to potentiate the development of CIA in L3T4-deficient mice or in animals transferred with collagen-primed spleen cells that were depleted of L3T4+ T cells. These results indicate that IL-1 beta readily accelerates the induction of arthritis when the disease is present, but that IL-1 beta is incapable of promoting the expression of the arthritis in the absence of underlying disease.
Subject(s)
Arthritis/etiology , Collagen/immunology , Interleukin-1/pharmacology , Animals , Antibodies/analysis , Antigens, Differentiation, T-Lymphocyte/analysis , Immunotherapy, Adoptive , Lymphocyte Depletion , Male , Mice , Mice, Inbred Strains , Species Specificity , T-Lymphocytes/physiologyABSTRACT
We previously demonstrated that treatments with rIL-1 beta accelerated the onset and progression of CIA in mice. In the present study, it was observed that IL-1 also enhanced the development of CIA in rats. Like the mouse model, maximal incidence (80-100%) of arthritis occurred within 7 days after the first treatment with IL-1 in rats. Thus, the acceleration of CIA by IL-1 (IL-1 CIA) may be an improved model for the rapid screening of anti-inflammatory and/or anti-arthritic drugs. As a first step to determining the utility of the IL-1 CIA model as a drug screen, we examined the ability of various known anti-inflammatory and anti-arthritic drugs to modify the IL-1 mediated enhancement of CIA in both rats and mice. The results of these studies showed that when analyzed in the IL-1 CIA model, rats and mice exhibited differences in their responses to several of these drugs. For example, dexamethasone, cyclophosphamide, azathioprine, various non-steroidal anti-inflammatory drugs (NSAIDs) as well as methotrexate were found active in the IL-1 CIA of rats. By contrast, the NSAIDs were found to be less effective in suppressing the IL-1 accelerated disease in mice. In both rats and mice, cyclosporine A and several disease modifying anti-arthritic drugs failed to the prevent the development of CIA that was potentiated by IL-1. Thus, in the IL-1 CIA model NSAIDs appeared to be less active in mice than rats. In conclusion, because of the shorter latent period required for the development of arthritis in the IL-1 treated animals, the IL-1 accelerated CIA model in both mice and rats may be useful for screening anti-inflammatory or anti-arthritic compounds.
