Cytokine production in synovial tissue of mice with collagen-induced arthritis (CIA)

Abstract

SUMMARYThe kinetics of cytokine production in arthritic limbs of mice with CIA was determined by using modified immunohistochemical techniques. Tissue cryostat sections of undecalcified whole paws were analysed for the presence of tumour necrosis factor-alpha (TNF-a), IL-6, IL-2, IL-4, IL-5 interferongamma (IFN-g), transforming growth factor-beta 2 (TGF-b2) and TGF-b3. Locally produced TNF-a, IL-6 and TGF-b2 were observed within the lining layer, sublining and pannus at all stages of disease. The staining of TNF-a was particularly intense at the cartilage-pannus junction. In contrast to the monokines, IFN-g and TGF-b3 were only expressed in scattered cells within the deeper layers of the synovia. Interestingly, IFN-g was not present in the late phase of CIA, despite the continued presence of TNF-a and IL-6 in the pannus. Production of IL-2, IL-4 or IL-5 was not detected in any joint. The observed pattern of a relative paucity of T cell-derived cytokines and an abundance of monokines during the late phase of T cell-dependent CIA indicates that the synovial cytokine pattern previously described in rheumatoid arthritis (RA) is fully compatible with a pathogenic role of T cells. The temporal as well as spatial dissociation between expression of T cell-derived cytokines and monokines indicates that T cell-independent mechanisms may also be of importance in the triggering of monokine production during arthritis.

Heterogeneous Effects of IL-2 on Collagen-Induced Arthritis

“…The observed increase in IL-2 mRNA contrasts with results from previous studies that were unable to detect IL-2 protein in RA synovial fluid or CIA joints (17,52). However, failure to detect IL-2 in the RA synovium may reflect the tendency of investigators to biopsy later in the disease course.…”

Lipoxin A4 Inhibits IL-1β-Induced IL-6, IL-8, and Matrix Metalloproteinase-3 Production in Human Synovial Fibroblasts and Enhances Synthesis of Tissue Inhibitors of Metalloproteinases

“…Synthetic LXA 4 was obtained from Cayman Chemical (Ann Arbor, MI). DMEM and cell culture reagents were from BioWhittaker (Walkersville, MD), with the exception of vitamin supplement obtained from Life Technologies (Grand Island, NY).…”

“…Human rIL-1␤ was purchased from Boehringer Mannheim (Indianapolis, IN). Rabbit LXA 4 receptor antiserum (␣LXA 4 R) was prepared as previously reported (17).…”

“…For example, TNF-␣ and IL-1 are potent agonists of human synovial fibroblast (SF) cell activation, a central mechanism of tissue damage in the inflamed joint (3,4). The active role of SF in the formation of the invasive rheumatoid pannus has been recently stressed by groups indicating the relevance of the synoviocyte synthesis of matrix metalloproteinase (5-7) and release of IL-6 (1, 8 -11), a cytokine that plays an essential pathogenetic role in animal models of RA (12).…”

“…These receptors, detected by RT-PCR and nested PCR using oligonucleotide primers derived from the sequence of the LXA 4 R expressed in cells of myeloid lineage (24), mediate LXA 4 suppression of IL-1␤-induced activation of human SF.…”