A murine interleukin-4-Ig fusion protein regulates the expression of Th1- and Th2-specific cytokines in the pancreas of NOD mice.

Abstract

Interleukin (IL)-4 is a key cytokine in T-helper type 2 (Th2) immune response. We have constructed a dimeric IL-4 molecule consisting of the murine IL-4 and the murine Fc part of IgG2a. We first tested the biological activity of the chimeric protein by in vitro studies using isolated murine spleen cells. IL-4-Ig was found to downregulate LPS-induced IFN-gamma and TNF-alpha production. The immunomodulatory potential of the fusion protein was also analyzed in non-obese diabetic (NOD) mice, an animal model for human type 1 diabetes. Female NOD mice aged 10 weeks were treated once with cyclophosphamide to accelerate and synchronize the progression of insulitis. Treatment with IL-4-Ig induced strong modulation of the pancreatic cytokine balance. Expression was downregulated for both Th1-specific cytokine IFN-gamma and the Th2-specific cytokine IL-10. IL-12p40 expression was only slightly affected. Interestingly, infiltration increased in the islets of IL-4-Ig-treated animals, and therefore did not correlate with the decreased IFN-gamma expression. Hence, IL-4-Ig did not prevent the progression from peri- to intra-insulitis, but suppressed inflammatory cytokine production. In most experiments, the biological activity of IL-4-Ig and IL-4 was comparable. We conclude that treatment with the chimeric protein IL-4-Ig effectively downregulates Th1 responses but simultaneously augments intra-islet infiltration.

• Authors: M Walz, L Overbergh, C Mathieu, H Kolb, S Martin
• Journal: Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme (Horm Metab Res) Vol. 34 Issue 10 Pg. 561-9 (Oct 2002) ISSN: 0018-5043 [Print] Germany
• PMID: 12439784 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin G
• RNA, Messenger
• Recombinant Fusion Proteins
• Tumor Necrosis Factor-alpha
• Interleukin-4
• Interferon-gamma

Topics

• Animals
• Baculoviridae (genetics, metabolism)
• Diabetes Mellitus, Type 1 (immunology, metabolism)
• Down-Regulation
• Female
• Immunoglobulin G (immunology, metabolism, pharmacology)
• Interferon-gamma (biosynthesis, immunology)
• Interleukin-4 (immunology, metabolism, pharmacology)
• Mice
• Mice, Inbred NOD
• Pancreas (immunology, metabolism)
• RNA, Messenger (biosynthesis, genetics)
• Recombinant Fusion Proteins (biosynthesis, genetics, pharmacology)
• Reverse Transcriptase Polymerase Chain Reaction
• Th1 Cells (immunology, metabolism)
• Th2 Cells (immunology, metabolism)
• Transfection
• Tumor Necrosis Factor-alpha (biosynthesis, immunology)