IL-6 antagonizes TGF-beta and abolishes immune privilege in eyes with endotoxin-induced uveitis.
OBJECTIVE
To determine the immunosuppressive status of aqueous humor (AqH) from mouse eyes afflicted with endotoxin-induced uveitis (EIU) and to identify the relevant cytokines responsible for immunomodulatory activity within EIU AqH.


METHODS
Bacterial lipopolysaccharide (LPS) was injected into hind footpads of C3H/HeN mice; and AqH, collected at 6, 12, 24, and 48 hours, was evaluated for content of transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and interferon (IFN)-gamma and capacity to suppress anti-CD3-driven T-cell proliferation. Cytokine mRNA expression in iris-ciliary body (I/CB) was analyzed by RNase protection assays.


RESULTS
During 6 to 24 hours after LPS injection, total TGF-beta levels in AqH increased even though the fluid lost its capacity to suppress T-cell activation. At this time, AqH contained high levels of IL-6, and I/CB contained high levels of IL-6 mRNA. When IL-6 was neutralized with specific antibodies, inflamed AqH reacquired its capacity to suppress T-cell activation, which correlated with high levels of TGF-beta. Coinjection of IL-6 plus antigen into the anterior chamber of the eye of normal mice prevented antigen-specific anterior chamber-associated immune deviation (ACAID).


CONCLUSIONS
LPS-induced intraocular inflammation is associated with local production of IL-6, which robs AqH of its immunosuppressive activity, perhaps by antagonizing TGF-beta. The fact that IL-6 antagonized ACAID induction in normal eyes suggests that strategies to suppress the intraocular synthesis of IL-6 may reduce inflammation and restore ocular immune privilege.
Schepens Eye Research Institute and Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114-0115, USA.
K
K
Ohta
S
S
Yamagami
A W
AW
Taylor
J W
JW
Streilein
D000818:Animals; D000867:Anterior Chamber / Q000187:drug effects / Q000276:immunology; D001082:Aqueous Humor / Q000187:drug effects* / Q000276:immunology; D018916:Blood-Aqueous Barrier / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D005260:Female; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000517:prevention & control; D015850:Interleukin-6 / Q000276:immunology / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D012486:Salmonella typhimurium; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014606:Uveitis, Anterior / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*
D016207:Cytokines; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta