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Interleukin-1ß and Tumor Necrosis Factor- Produce Distinct, Time-dependent Patterns of Acute Arthritis in the Rat Knee ¹

Departments of Pathology (BB, DD) and Inflammation Research (GC, LZ, DZ, UF), Amgen, Inc., One Amgen Center Drive, M/S 29-M-B, Thousand Oaks, CA

Interleukin-1ß (IL-1ß) and tumor necrosis factor- (TNF-) synergistically induce and sustain arthritis. Two competing hypotheses of arthritis induction are 1) that TNF preferentially mediates inflammation, whereas IL-1 impels bone destruction, or 2) that either cytokine controls the entire process. In this study, these propositions were tested in two experiments by instilling IL-1ß or TNF- into one knee of Lewis rats (n = 6/group) to incite arthritis, after which semiquantitative scores for inflammation, bone resorption, osteoclasts, and cartilage integrity were acquired. In the induction study, IL-1ß or TNF- (3, 10, or 30 µg) was given once to incite arthritis. After 2 days, IL-1ß induced significant, dose-dependent increases in inflammation (mild to marked), bone resorption (minimal to moderate), and osteoclasts (minimal to moderate). In contrast, TNF- induced minimal to mild inflammation but had little impact on resorption or osteoclasts. Both IL-1 and TNF (10 µg) yielded mild cartilage degeneration. Most lesion scores in TNF-treated rats were significantly lower than those in animals given the same dose of IL-1ß. In the persistence study, rats were injected once with IL-1 or TNF (10 µg) and maintained for 2, 3, or 7 days. IL-1ß significantly enhanced inflammation (all 3 days), bone resorption (days 2 and 3), osteoclasts (days 2 and 3), and cartilage matrix loss (days 2 and 3), whereas TNF- augmented inflammation (days 2 and 3) and cartilage degeneration (day 2) but not bone resorption or osteoclasts. Thus, both IL-1ß and TNF- can launch inflammation, but IL-1ß drives skeletal destruction.

Key words: Arthritis; cytokine; IL-1; intra-articular; TNF.

Request reprints from U. Feige, Amgen Inc., One Amgen Center Drive, M/S 29-M-B, Thousand Oaks, CA 91320-1799 (USA). ufeige{at}amgen.com.