Transient gene transfer of IL-12 regulates chemokine expression and disease severity in experimental arthritis.
Murine collagen-induced arthritis (CIA) is characterized by pannus formation, cell infiltration, and cartilage erosion, and shares histologic and immunologic features with rheumatoid arthritis. Numerous cytokines are reportedly associated with RA and/or CIA; however, their mechanistic role is not clear. To determine the role of IL-12 in CIA, DBA/1 LacJ mice were administered 3 x 10(8) plaque-forming units of mIL-12 i.p. in a nonreplicating adenoviral vector (AdIL-12) on day 25 following primary type II collagen immunization. Our studies demonstrated that systemic transient overexpression of IL-12 accelerated disease progression and augmented the arthritis severity relative to mice expressing a replication-deficient, E1-deleted Ad5 construct. A likely mechanism for this increase in pathology was the increase in the expression of cytokines and chemokines known to play a proinflammatory role in disease. In particular, levels of murine IFN-gamma were significantly increased in mice overexpressing AdIL-12 relative to the replication-deficient, E1-deleted Ad5 construct. Interestingly, the C-X-C chemokine murine macrophage inflammatory protein-2, as well as the C-C chemokines murine monocyte chemoattractant protein-1 and murine macrophage inflammatory protein-1alpha were up-regulated by AdIL-12 relative to controls. In an additional set of studies, neutralization of endogenous IL-12 in CIA mice was shown to delay disease onset and attenuate disease severity. IFN-gamma levels in the mice receiving anti-IL-12 were significantly decreased in joint homogenates. These studies demonstrate that IL-12 is an important cytokine involved in controlling the production of chemokines/cytokines leading to the evolution of experimental arthritis.
Parks
E
E
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109, USA.
Strieter
R M
RM
Lukacs
N W
NW
Gauldie
J
J
Hitt
M
M
Graham
F L
FL
Kunkel
S L
SL
D000256:Adenoviridae; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology*; D003094:Collagen; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D018664:Interleukin-12 / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA
D018925:Chemokines; D018664:Interleukin-12; D003094:Collagen