Interleukin-1beta and tumor necrosis factor-alpha produce distinct, time-dependent patterns of acute arthritis in the rat knee.
Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) 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-1beta or TNF-alpha 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-1beta or TNF-alpha (3, 10, or 30 micro g) was given once to incite arthritis. After 2 days, IL-1beta induced significant, dose-dependent increases in inflammation (mild to marked), bone resorption (minimal to moderate), and osteoclasts (minimal to moderate). In contrast, TNF-alpha induced minimal to mild inflammation but had little impact on resorption or osteoclasts. Both IL-1 and TNF (>/=10 micro g) yielded mild cartilage degeneration. Most lesion scores in TNF-treated rats were significantly lower than those in animals given the same dose of IL-1beta. In the persistence study, rats were injected once with IL-1 or TNF (10 micro g) and maintained for 2, 3, or 7 days. IL-1beta 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-alpha augmented inflammation (days 2 and 3) and cartilage degeneration (day 2) but not bone resorption or osteoclasts. Thus, both IL-1beta and TNF-alpha can launch inflammation, but IL-1beta drives skeletal destruction.
Bolon
B
B
Department of Pathology, Amgen Inc., One Amgen Center Drive, M/S 29-M-B, Thousand Oaks, CA 91320-1799, USA.
Campagnuolo
G
G
Zhu
L
L
Duryea
D
D
Zack
D
D
Feige
U
U
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000473:pathology*; D001862:Bone Resorption / Q000139:chemically induced; D002356:Cartilage / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006614:Hindlimb / Q000473:pathology*; D006652:Histological Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D007596:Joints / Q000473:pathology*; D008297:Male; D010010:Osteoclasts / Q000187:drug effects; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha