Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes
Andreas Holz, … , Kelly Brett, Michael B.A. Oldstone
Andreas Holz, … , Kelly Brett, Michael B.A. Oldstone
Published December 15, 2001
Citation Information: J Clin Invest. 2001;108(12):1749-1758. https://doi.org/10.1172/JCI13915.
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Article

Constitutive β cell expression of IL-12 does not perturb self-tolerance but intensifies established autoimmune diabetes

Abstract

To analyze the function of the Th1-promoting cytokine IL-12 in vivo, we generated transgenic (tg) mice (RIP-IL12 mice) whose pancreatic β cells constitutively express bioactive IL-12 or one of its components, p35 or p40. In contrast to non-tg littermates or single-tg RIP-p35 and RIP-p40 mice, RIP-IL12 mice developed a marked pancreatic infiltration of lymphocytes and macrophages, mainly around islets. Expression of bioactive IL-12 primarily upregulated transcript levels of IFN-inducible protein-10 (IP-10), RANTES, IFN-γ, and TNF-α in the pancreas. Despite the substantial recruitment of mononuclear cells, no biochemical or clinical disease was evident in the exocrine or endocrine pancreas. Coexpression of lymphocytic choriomeningitis virus (LCMV) proteins with IL-12 in the β cells failed to spontaneously activate or expand antigen-specific anti-self/viral T cells in uninfected tg animals. However, when RIP-IL12 × RIP-LCMV tg mice were infected with LCMV, antigen-specific anti-self/viral T cells were induced, which led to an acceleration in the kinetics and severity of insulin-dependent diabetes mellitus (IDDM). Thus, the ectopic expression of IL-12 does not spontaneously break tolerance and activate antigen-specific T cells in the periphery, but it does worsen ongoing autoimmune disease.

Authors

Andreas Holz, Kelly Brett, Michael B.A. Oldstone

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Expression of cytokine and chemokine transcripts in pancreata of RIP-IL1...
Expression of cytokine and chemokine transcripts in pancreata of RIP-IL12 tg mice. RNA was obtained from the pancreata of RIP-IL12 (n = 7), RIP-p35 (n = 3), and RIP-p40 (n = 4) tg mice and non-tg mice (n = 3). (a) RPA showed upregulation of IFN-γ, TNF-α, and LT-β in the pancreas of RIP-IL12 tg mice. All protected fragments were normalized against L32 RNA levels. (b) Shown are all transcripts analyzed, with the mean expression levels ± SEM, and (last column) fold increase in transcription measured in RIP-IL12 tg mice over that in non-tg littermates. The Th2 cytokines IL-4, IL-5, IL-9, and IL-13 remained undetectable in all groups, whereas Th1 cytokines were markedly elevated. (c) By FACS analysis, lymphocytes isolated from the pancreata of RIP-IL12 tg mice produced primarily IFN-γ and TNF-α Th1 cytokines, but not the Th2 cytokine IL-4 after stimulation with PMA and ionomycin. The y axis represents the cytokine detected, and the x axis shows CD4 detection. Values display the frequency of cytokine expression among the CD4+ T cell population. IL-1Rα, IL-1 receptor α. NIL, not detectable; TCA-3, T cell activation gene-3; MIF, macrophage migration inhibitory factor.