IL-1 and TNF receptor-deficient mice show decreased inflammation in an immune complex model of uveitis.
OBJECTIVE
To determine the role of interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) in the induction of uveitis by a reverse passive Arthus reaction (RPAR).


METHODS
Human serum albumin (HSA) antiserum was injected into the vitreous of "knockout" or "double knockout" mice genetically deficient in IL-1 receptor type I (IL-1RI-/-), TNF receptors p55 and p75 (TNFR p55-/-/p75-/-), IL-1RI and TNFR p55 (IL-1RI-/-/TNFR p55-/-), and controls. Twenty-four hours later, animals were challenged with intravenous HSA. Eyes were enucleated 4 hours after antigen challenge, and inflammation was quantitated by counting cells on histologic sections. Interleukin-6 in aqueous humor was measured with a B9 cell bioassay. The distribution of immune complexes in eyes was observed by immunohistochemical staining for IgG and complement component C3.


RESULTS
Four hours after antigen challenge, immune complexes were localized at the ciliary body and iris of receptor-deficient mice. A transient uveitis was most severe at this time. A significant reduction in the median number of infiltrating cells was found in TNFR p55-/-/p75-/- mice (4.8, n = 15), compared with controls (14.2, n = 20, P < 0.05). The median number of infiltrating cells was significantly reduced in IL-1RI-/- mice (knockout 2.6, n = 11; controls 7.4, n = 8, P < 0.005). Interleukin-1RI-/-/TNFR p55-/- mice had a strong reduction in infiltrating cells (knockout 1.6, n = 11; controls 27.3, n = 12, P = 0.002). Interleukin-6 activity in aqueous humor was reduced in IL-1RI-/-/TNFR p55-/- mice (P = 0.03) but not in TNFR p55-/-/p75-/- (P = 0.40) mice. Most IL-1RI-/-mice had no detectable aqueous humor IL-6, but this group was not statistically different from controls.


CONCLUSIONS
In contrast to endotoxin-induced uveitis, both IL-1 and TNF appear to have critical roles in RPAR uveitis. When receptors for these cytokines were deleted, the severity of immune complex-induced uveitis was profoundly reduced.
Brito
B E
BE
Department of Ophthalmology, Casey Eye Institute, Oregon Health Sciences University, Portland 97201-4197, USA.
O'Rourke
L M
LM
Pan
Y
Y
Anglin
J
J
Planck
S R
SR
Rosenbaum
J T
JT
D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology*; D001082:Aqueous Humor / Q000737:chemistry; D001183:Arthus Reaction / Q000276:immunology; D003176:Complement C3 / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000032:analysis; D015850:Interleukin-6 / Q000032:analysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017472:Receptors, Interleukin-1 / Q000172:deficiency / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000502:physiology*; D012709:Serum Albumin; D014606:Uveitis, Anterior / Q000209:etiology / Q000276:immunology* / Q000473:pathology
D000936:Antigen-Antibody Complex; D003176:Complement C3; D007074:Immunoglobulin G; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D012709:Serum Albumin