Regulation of transforming growth factor-beta production by interleukin-12.
The induction of peripheral tolerance following oral antigen administration in several autoimmune disease and conventional animal models correlates with the production of transforming growth factor-beta (TGF-beta) and T helper type 2 (Th2) cytokines. The factors regulating TGF-beta production and its relation to the Th2 response, however, have not been defined. We demonstrate that the systemic administration of antibodies to interleukin (IL)-12 to ovalbumin (OVA)-T cell receptor (TCR) transgenic mice fed high doses of OVA, followed by systemic OVA challenge, substantially enhances TGF-beta, but not IL-4 production by peripheral T cells. Furthermore, we demonstrate in an in vitro T cell differentiation model that naive (CD4+/Mel-14hi) OVA-TCR-T cells stimulated with OVA-pulsed dendritic cells (DC) produce four- to fivefold higher amounts of TGF-beta when cultured with anti-IL-12 or anti-interferon-gamma (IFN-gamma). In this in vitro system, IL-4 was not required for TGF-beta production by T cells; however, it appeared to enhance levels of TGF-beta by promoting the growth of TGF-beta-producing cells. Our findings demonstrate that IL-12 and IFN-gamma are important negative regulators of TGF-beta production both in vivo and in vitro, and that their modulation may be of benefit for the treatment of autoimmune disorders.
Marth
T
T
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-1890, USA.
Strober
W
W
Seder
R A
RA
Kelsall
B L
BL
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology*; D015847:Interleukin-4 / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000187:drug effects
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D011948:Receptors, Antigen, T-Cell; D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma; D010047:Ovalbumin