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S. Masli, B. Turpie, J.W. Streilein; By Altering TNFR2:TNFR1 Expression, TGFb Prevents ACAID-inducing Antigen Presenting Cells from Secreting IL-12 . Invest. Ophthalmol. Vis. Sci. 2003;44(13):990.
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Purpose. TGFß2-treated APCs are required to produce TNFα in order to induce ACAID. We wished to determine if these APCs also alter their expression of TNFα receptors (CD120a - TNFR1-p55, CD120b - TNFR2-p75) and promote ACAID through autocrine stimulation. Methods. Macrophage hybridoma #59 cells were pulsed with ovalbumin (OVA) and cultured in the presence of TGFß2 (5 ng/ml) and/or anti-TNFR1 antibody (agonist or blocking). The cells were examined (a) in vitro by RT-PCR, for expression of genes CD120a and CD120b, and by flow cytometry for TNFR2 expression; and (b) in vivo for their capacity to suppress OVA-specific delayed hypersensitivity (DH) when injected into naïve mice immunized subsequently with OVA plus complete Freunds’ adjuvant. Thioglycolate-elicited PECs from TNFR2 KO or wild-type mice were tested for their ability to promote ACAID and to inhibit IL-12 secretion upon treatment with TGFß2. IL-12 content of culture supernatants was measured by ELISA. Results. Wild-type APCs treated with TGFß2, up-regulated message for TNFR2 (p75) and increased expression of this receptor on their cell surface, but down-regulated message for TNFR1 (p55) whose surface expression was reduced, thereby changing the ratio of the 2 receptors in favor of TNFR2. Unlike wild-type APCs, OVA-pulsed, TGFß2-treated TNFR2-deficient APCs failed to induce ACAID in vivo, and secreted large amounts of IL-12 in vitro. Anti-TNFR1 agonist antibody treatment of TGFß2-exposed APCs abolished their ability to suppress DH responses in vivo, whereas TGFß2-treated APCs exposed anti-TNFR I blocking antibody readily induced ACAID.. Conclusions. TGFß2 exposure of APCs induces TNFα production and shifts the ratio of TNFR1:TNFR2, favoring the latter. Autocrine TNFα signaling through TNFR2 inhibits IL-12 production and enables the APCs to induce ACAID when injected into naïve mice.
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