Analysis of immunomodulatory activities of aqueous humor from eyes of mice with experimental autoimmune uveitis.
Aqueous humor (AqH) contains immunosuppressive factors, especially TGF-beta2, that contribute to the immune privileged status of the anterior chamber. However, this may not be true when the blood-ocular barrier is compromised by ocular inflammation. To determine the immunosuppressive status of AqH from murine eyes afflicted with experimental autoimmune uveitis, B10.A mice were immunized with interphotoreceptor retinoid-binding protein. AqH was collected from eyes of affected mice periodically after immunization and then evaluated for content of TGF-beta, proinflammatory cytokines, and the capacity to suppress anti-CD3-driven T cell proliferation. mRNA expression of selected cytokines in iris and ciliary body from inflamed eyes was analyzed by ribonuclease protection assay. We found that TGF-beta levels were significantly increased in AqH from EAU eyes on days 11, 17, and 28. AqH collected on day 11 (onset of disease) failed to suppress T cell proliferation and contained large amounts of locally produced IL-6 that antagonized TGF-beta. In contrast, AqH collected at 17 days (when ocular inflammation was progressively severe) re-expressed the ability to suppress T cell proliferation, in this case due to high levels of blood-derived TGF-beta1 and eye-derived TGF-beta2 in the absence of IL-6. Thus, during the onset of experimental autoimmune uveitis, the ocular microenvironment loses its immunosuppressive properties due to local production of IL-6. But as inflammation mounts, AqH IL-6 content falls, and the fluid reacquires sufficient TGF-beta eventually to suppress immunogenic inflammation. The paradoxical roles of IL-6 in antagonizing TGF-beta, while promoting TGF-beta accumulation during ocular inflammation, is discussed.
Ohta
K
K
Schepens Eye Research Institute, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
Wiggert
B
B
Yamagami
S
S
Taylor
A W
AW
Streilein
J W
JW
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D002924:Ciliary Body / Q000378:metabolism; D005260:Female; D007106:Immune Sera / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D018836:Inflammation Mediators / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007498:Iris / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014606:Uveitis, Anterior / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
D000276:Adjuvants, Immunologic; D017252:CD3 Complex; D007106:Immune Sera; D007166:Immunosuppressive Agents; D018836:Inflammation Mediators; D015850:Interleukin-6; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta