PARENT SESSION

(154) RELAXIN DECREASES TUMOR NECROSIS FACTOR- (TNF-) IN CHRONIC AND ACUTE RAT MODELS OF JOINT INFLAMMATION.

Santora, Karen^{1, 2}, O'Byrne, Elizabeth^{2, 3}, Visco, Denise¹, Steinetz, Bernard⁴, Bagnell, Carol², ¹ Merck & Co., Inc., Rahway, NJ² Rutgers University, New Brunswick, NJ³ Novartis Institute for Biomedical Research, East Hanover, NJ⁴ New York University School of Medicine, Tuxedo, NY

ABSTRACT- Pregnancy reduces the incidence and severity of rheumatoid arthritis (RA). TNF- is a pro-inflammatory cytokine elevated in the synovial fluid of RA patients. Relaxin (RLX), a hormone of pregnancy, inhibits endotoxin-induced TNF- release from human THP-1 cells. Studies indicate that estradiol valerate (EV) priming and daily RLX reduce disease severity in a chronic, 21-day rat adjuvant-induced arthritis (RAA) model of RA. This combination of hormones decreased paw inflammation and radiographic joint damage compared to arthritic controls. The objectives of this study were to investigate the impact of RLX alone and in combination with EV on: (1) systemic pro-inflammatory and anti-inflammatory cytokines in the chronic RAA model and (2) synovial fluid TNF- in an acute rat model of endotoxin-induced joint inflammation. In the RAA model, ovariectomized Lewis rats (n=8/group) were treated with EV (5 ug/sc in sesame oil/week, starting day -10), porcine RLX (8 ug/sc in 1.0% benzopurpurin (BP)/day, starting day -3), EV plus RLX, or vehicle (sesame oil/BP). Arthritis was induced on day 0 by adjuvant injection into the left hind foot. On day 21 blood was collected for analysis of circulating TNF-, interleukin (IL)-1 and IL-10. Both EV and RLX alone decreased circulating TNF- (P<0.05). However, EV primed, RLX-treated rats showed a greater decline in TNF- than rats treated with EV alone (P<0.05). There was no effect of hormones on the pro-inflammatory cytokine, IL-1, whereas IL-10, an anti-inflammatory cytokine, increased in response to EV and EV plus RLX (P<0.05). In the acute inflammation model, female Lewis rats (n=6/group) were treated with EV (5 ug/sc, day -7), porcine RLX (8 ug/sc) on day -1 and 0, EV plus RLX, or vehicle. On day 0, knee joint inflammation was induced by intra-articular injection of lipopolysaccharide (LPS;10 ug/0.5 ml) and TNF- was measured in synovial fluid 2h later. The results showed no effect of EV or RLX alone on LPS-induced synovial fluid TNF-. However, in rats primed with EV and treated with RLX there was a reduced TNF- response to LPS (P< 0.05). These data in chronic and acute rat models of joint inflammation suggest that RLX, in concert with estrogen, by decreasing TNF- could play a role in reducing RA-induced inflammation during pregnancy by an effect on the immune system.

KEY WORDS: relaxin, estrogen, tumor necrosis factor-, joint inflammation