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

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Abstract
Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) 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-1β or TNF-α 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-1β or TNF-α (3, 10, or 30 μg) was given once to incite arthritis. After 2 days, IL-1β induced significant, dose-dependent increases in inflammation (mild to marked), bone resorption (minimal to moderate), and osteoclasts (minimal to moderate). In contrast, TNF-α 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-1β. In the persistence study, rats were injected once with IL-1 or TNF (10 μg) and maintained for 2, 3, or 7 days. IL-1β 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-α augmented inflammation (days 2 and 3) and cartilage degeneration (day 2) but not bone resorption or osteoclasts. Thus, both IL-1β and TNF-α can launch inflammation, but IL-1β drives skeletal destruction.

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