Deoxyhypusine synthase promotes differentiation and proliferation of T helper type 1 (Th1) cells in autoimmune diabetes.

Abstract

In type 1 diabetes, cytokines arising from immune cells cause islet β cell dysfunction even before overt hyperglycemia. Deoxyhypusine synthase catalyzes the crucial hypusine modification of the factor eIF5A, which promotes the translation of a subset of mRNAs involved in cytokine responses. Here, we tested the hypothesis that deoxyhypusine synthase and, secondarily, hypusinated eIF5A contribute to the pathogenesis of type 1 diabetes using the non-obese diabetic (NOD) mouse model. Pre-diabetic NOD mice that received injections of the deoxyhypusine inhibitor N1-guanyl-1,7-diaminoheptane (GC7) demonstrated significantly improved glucose tolerance, more robust insulin secretion, and reduced insulitis compared with control animals. Analysis of tissues from treated mice revealed selective reductions in diabetogenic T helper type 1 (Th1) cells in the pancreatic lymph nodes, a primary site of antigen presentation. Isolated mouse CD90.2(+) splenocytes stimulated in vitro with anti-CD3/anti-CD28 and IL-2 to mimic autoimmune T cell activation exhibited proliferation and differentiation of CD4(+) T cell subsets (Th1, Th17, and Treg), but those treated with the deoxyhypusine synthase inhibitor GC7 showed a dose-dependent block in T cell proliferation with selective reduction in Th1 cells, similar to that observed in NOD mice. Inhibition of deoxyhypusine synthase blocked post-transcriptional expression of CD25, the high affinity IL-2 receptor α chain. Our results suggest a previously unrecognized role for deoxyhypusine synthase in promoting T cell proliferation and differentiation via regulation of CD25. Inhibition of deoxyhypusine synthase may provide a strategy for reducing diabetogenic Th1 cells and preserving β cell function in type 1 diabetes.

• Authors: Stephanie C Colvin, Bernhard Maier, David L Morris, Sarah A Tersey, Raghavendra G Mirmira
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 51 Pg. 36226-35 (Dec 20 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 24196968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Insulin
• Interleukin-2 Receptor alpha Subunit
• N(1)-guanyl-1,7-diaminoheptane
• Guanine
• Oxidoreductases Acting on CH-NH Group Donors
• deoxyhypusine synthase

Topics

• Animals
• Blood Glucose
• Cell Differentiation
• Cell Proliferation
• Diabetes Mellitus, Type 1 (enzymology, immunology, metabolism)
• Guanine (analogs & derivatives, pharmacology)
• Insulin (blood)
• Insulin Resistance
• Interleukin-2 Receptor alpha Subunit (metabolism)
• Lymph Nodes (cytology, metabolism)
• Mice
• Mice, Inbred NOD
• Oxidoreductases Acting on CH-NH Group Donors (antagonists & inhibitors, metabolism)
• T-Lymphocytes, Regulatory (cytology, metabolism)
• Th1 Cells (cytology, enzymology, immunology)
• Th17 Cells (cytology, metabolism)