Faculty Research 1990 - 1999

Title

Hematopoietic stem-cell defects underlying abnormal macrophage development and maturation in NOD/Lt mice: defective regulation of cytokine receptors and protein kinase C.

Document Type

Article

Publication Date

1993

Keywords

Antigen-Presenting-Cells: ph, Bone-Marrow: cy, Cytokines: ph, Diabetes-Mellitus-Insulin-Dependent: pp, pa, Enzyme-Induction, Female, Gene-Expression, Genes-MHC-Class-II, Haplotypes, Hematopoietic-Stem-Cells: ph, Interleukin-1: bi, Macrophages: ph, Mice, Mice-Inbred-NOD: ph, Protein-Kinase-C: ph, Receptors-Interferon: ge, Receptors-Macrophage-Colony-Stimulating-Factor: ge, RNA-Messenger: ge, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S, Tumor-Necrosis-Factor: bi

JAX Source

Proc Natl Acad Sci U S A 1993 Oct 15;90(20):9625-9

Grant

DK27722/DK/NIDDK, DK36175/DK/NIDDK

Abstract

The immunopathogenesis of autoimmune insulin-dependent diabetes in NOD mice entails defects in the development of macrophages (M phi s) from hematopoietic precursors. The present study analyzes the cellular and molecular basis underlying our previous finding that the Mo growth factor colony-stimulating factor 1 (CSF-1) promotes a reduced level of promonocyte proliferation and M phi development from NOD bone marrow. CSF-1 stimulation of NOD marrow induced Mos to differentiate to the point that they secreted levels of tumor necrosis factor alpha equivalent to that of controls. However, CSF-1 failed to prime NOD M phi s to completely differentiate in response to gamma-interferon, as shown by their decreased lipopolysaccharide-stimulated interleukin 1 secretion. These defects, in turn, were associated with an inability of CSF-1 to up-regulate c-fms (CSF-1 receptor) and Ifgr (gamma-interferon receptor) expression. Even though the combination of CSF-1 and gamma-interferon up-regulated c-fms and Ifgr transcript levels in NOD M phi s to levels induced in control M phi s by CSF-1 alone, the protein kinase C activities coupled to these receptors remained 4-fold lower in NOD M phi s than in M phi s derived from the marrow of diabetes-resistant NON and SWR control mice. Despite expressing the diabetogenic H-2g7 haplotype, M phi s derived from cytokine-stimulated marrow of the NON.H-2g7 congenic stock were functionally more mature than similarly derived M phi s from NOD mice. Whereas diabetes resistance was abrogated in 67% of irradiated (NOD x NON)F1 females reconstituted with NOD marrow, no recipients became diabetic after reconstitution with a 1:1 mixture of marrow from NOD and the congenic stock. Thus, failure to develop functionally mature monocytes may be of pathogenic significance in NOD mice.

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