Membrane-Associated IL-1 Contributes to Chronic Synovitis and Cartilage Destruction in Human IL-1α Transgenic Mice

Abstract

IL-1 molecules are encoded by two distinct genes, IL-1α and IL-1β. Both isoforms possess essentially identical activities and potencies, whereas IL-1α, in contrast to IL-1β, is known to act as a membrane-associated IL-1 (MA-IL-1) and plays an important role in a variety of inflammatory situations. The transgenic (Tg) mouse line (Tg1706), which was generated in our laboratory, overexpresses human IL-1α (hIL-1α) and exhibits a severe arthritic phenotype characterized by autonomous synovial proliferation with subsequent cartilage destruction. Because the transgene encoded Lys64 to Ala271 of the hIL-1α amino acid sequence, Tg mice may overproduce MA-IL-1 as well as soluble IL-1α. The present study investigated whether MA-IL-1 contributes to synovial proliferation and cartilage destruction in the development of arthritis. Flow cytometric analysis revealed that both macrophage-like and fibroblast-like synoviocytes constitutively produce MA-IL-1. D10 cell proliferation assay revealed MA-IL-1 bioactivity of paraformaldehyde-fixed synoviocytes and the further induction of endogenous mouse MA-IL-1 via autocrine mechanisms. MA-IL-1 expressed on synoviocytes triggered synoviocyte self-proliferation through cell-to-cell (i.e., juxtacrine) interactions and also promoted proteoglycan release from the cartilage matrix in chondrocyte monolayer culture. Interestingly, the severity of arthritis was significantly correlated with MA-IL-1 activity rather than with soluble IL-1α activity or concentration of serum hIL-1α. Moreover, when the Tg1706 line was compared with the Tg101 line, which selectively overexpresses the 17-kDa mature hIL-1α, the severity of arthritis was significantly higher in the Tg1706 line than in the Tg101 line. These results suggest that MA-IL-1 contributes to synoviocyte self-proliferation and subsequent cartilage destruction in inflammatory joint disease such as rheumatoid arthritis.

17β-Estradiol Induces IL-1α Gene Expression in Rheumatoid Fibroblast-Like Synovial Cells through Estrogen Receptor α (ERα) and Augmentation of Transcriptional Activity of Sp1 by Dissociating Histone Deacetylase 2 from ERα

“…In type II collagen-induced arthritis, IL-1␤ plays a major role in the outcome of arthritis (18,46). In IL-1␣ transgenic mice, however, membrane-bound IL-1␣ from synoviocytes appeared to be critical for the induction of arthritis (23). Interestingly, the severity of arthritis was correlated with the expression level of membrane-bound IL-1␣ rather than serum IL-1␣ or IL-1␤.…”

“…IL-1␣ is reportedly predominant in the early phase of arthritis and participates in the inhibition of proteoglycan synthesis (25). Interestingly, membrane bound IL-1␣ in the synovial cells, but not soluble IL-1␣, is important in the spontaneous outcome of the arthritis in IL-1␣ transgenic mice (23).…”

“…Although they exert the same biological activities by binding to the same receptors (IL-1R), the precursor of IL-1␣ can bind to IL-1R and exert biological activities, whereas that of IL-1␤ binds very weakly to IL-1R and cannot exert biological effects (22). Thus, IL-1␤ works after proteolytic maturation following the release from its producing cells, while IL-1␣ can exert the biological activity even in the membrane-bound form (23). Both isoforms appear to play a pivotal role in cartilage destruction, while it has been reported that IL-1␤ plays a more dominant role in established collagen-induced agonist based on evidence of the marked inhibitory effects of anti-IL-1␤ treatment (18) or IL-1-converting enzyme inhibitor (24).…”

Comprehensive association study of genetic variants in the IL-1 gene family in systemic juvenile idiopathic arthritis

“…Although the effects of IL-1b are more widely investigated there is evidence that IL-1a is important in arthritis development and progression. This includes the observation that levels of membrane-bound IL-1a, but not serum IL-1a or IL-1b, correlate with the severity of arthritis in a mouse model, 37 and that RA patients producing anti-IL-1a antibodies develop a less destructive disease. 38 Dysregulation of the IL1A gene could lead to a perpetuation of the local inflammatory process, contributing to the development of a chronic inflammatory state.…”

Dihydrotestosterone Inhibits Tumor Necrosis Factor .ALPHA. Induced Interleukin-1.ALPHA. mRNA Expression in Rheumatoid Fibroblast-Like Synovial Cells

“…[8][9][10] By the experiments using animal model of arthritis IL-1a appeared to be important in the early phase of arthritis and participates in the inhibition of proteoglycan synthesis. 11,12) Although it is not clarified how and what causes RA, RA is deviated to women as also observed in other autoimmune diseases; the ratio of RA incidence in women to men is about 4 : 1. The levels of estrogen to androgen in synovial fluid are elevated in both male and female RA patients 13) and the level of testosterone in serum and synovial fluid is lower in male RA patients as compared to normal individuals.…”