Interleukin-1␤ (IL-1␤

Objective. To determine the consequences of pharmacologic up-regulation of heme oxygenase 1 (HO-1), and inhibition of HO-1 by injection of an anti-HO-1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis.Methods. In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO-1 was up-regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin-1␤ (IL-1␤), IL-6, tumor necrosis factor ␣ (TNF␣), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E 2 (PGE 2 ) production, and matrix metalloproteinase 9 (MMP-9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes.Results. Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP-induced expression of HO-1 in the joints and liver was associated with marked decreases in IL-1␤, IL-6, and TNF␣ levels, PGE 2 secretion, and MMP-9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO-1 induction. Specific inhibition of HO-1 by in vivo delivery of anti-HO-1 siRNA repressed the protective effects.Conclusion. Our data provide the first evidence that pharmacologically induced up-regulation of HO-1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO-1 may have potential as therapy in the acute phase of inflammatory arthritis in humans.

Objective. To determine whether peroxisome proliferator-activated receptor ␣ (PPAR␣) agonists protect chondrocytes against the effects of interleukin-1␤ (IL-1␤).Methods. PPAR␣ expression and function in cultured rabbit articular chondrocytes were studied by Northern blotting, electrophoretic mobility shift assay, Conclusion. Our findings support the notion that there is a PPAR␣-dependent mechanism that inhibits IL-1␤ function in chondrocytes, which operates via an increase in sIL-1Ra production.

A direct effect of sex steroid hormones on in vitro cartilage cell metabolism was demonstrated. Cells were derived from rabbit fetuses on day 20 of gestation, and from male and female rabbits aged from 2 to 80 days. Testosterone (T), dihydrotestosterone (DHT), or 17 beta-estradiol (E2) (10(-9) -10(-9) M) were added to primary culture of epiphyseal articular chondrocytes. They showed an age-dependent stimulatory effect on [35S]sulfate incorporation into newly synthesized proteoglycans. In cultured rabbit fetal cartilage cells, the maximum active concentration of T and DHT was 10(-9) M with a 40% stimulating effect over control values. E2 was even more active with 80% stimulating effect when added at 10(-8) M. Chondrocytes from animals aged up to 5 days responded poorly and those from animals aged 5-30 days not at all. The response of cells from older animals varied with animal age and sex. T and DHT stimulated chondrocytes from males aged 32-55 days and females aged 40-52 days to about the same extent. E2 stimulated cells from animals of the same ages, but the response of female-derived cells was twice that of male-derived cells. The stimulating effect was dose dependent from 10(-11) to 10(-8) M and maximal at 10(-9) M for T and DHT and at 10(-8) M for E2. Puromycin completely abolished the effect.

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Anulus fibrosus cells can be stimulated by interleukin 1 beta to produce factors implicated in local degradative and inflammatory processes. This production is associated with decreased proteoglycan aggregation. Anulus fibrosus cells respond slightly less well to interleukin 1 beta in vitro than do articular cells.

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Summary ― Prepubertal rabbit epiphyseal chondrocytes were grown in high density primary culture for 3 d. They were then incubated for 3 additional d in serum-free culture medium to which bFGF (1-50 ng/ml) was added. During the last 24 h incubation period, either IGF,