T Cell Protein Tyrosine Phosphatase (TC-PTP) and Protein Tyrosine Phosphatase (PTP)-1B are two closely related enzymes involved in the regulation of cytokine signalling. While tcptp-/- mice display a wide range of hematopoietic defects and die within three to five weeks after birth, ptp1b-/- mice are healthy and show no apparent immune phenotype; nevertheless, in vitro results suggest that both enzymes negatively regulate interferon signalling. The goal of my thesis was to determine their role in macrophages whose activation and maturation is largely dependent on interferon-gamma. / In the first instance, we detected a progressive mononuclear cellular infiltrate in several organs of the TC-PTP deficient mice, which, together with active cytokine production, was likely to be the cause of tissue damage and ultimately their death. Moreover, the tcptp-/- mice showed increased sensitivity to exogenous lipopolysaccharide in vivo and developed symptoms of septic shock. tcptp-/- spleen-derived macrophages were also highly sensitive to lipopolysaccharide. These findings indicated that TC-PTP was necessary for the regulation of inflammatory disease. / In the second part, although ptp1b-/- bone marrow presented no abnormalities at the myeloid progenitor level, it contained more colony stimulating factor (CSF)-1 -responsive cells and the CSF-1 receptor was hyperphosphorylated in ptp1b-/- bone marrow-derived macrophages. ptp1b-/- splenic macrophages also displayed upregulated activation markers as well as increased sensitivity to LPS. Collectively, these results indicated that PTP-1B regulated myeloid differentiation and macrophage activation in vivo. / Lastly, we wished to delete one or both copies of PTP-1B in tcptp-/- and tcptp+/-mice by interbreeding to study the redundancy of the two enzymes. Our results indicated that the double mutant was lethal at a relatively early stage of embryonic development. Mice heterozygous for TC-PTP on the ptp1b-/- background developed symptoms similar to the tcptp-/- mice, and their macrophages were highly sensitive to interferon-gamma as shown by increased Stat1 phosphorylation, indicating a nonredundant role for PTP-1B and TC-PTP in the regulation of interferon signalling.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.100624 |
| Date | January 2006 |
| Creators | Heinonen, Krista. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | © Krista Heinonen, 2006 |
| Relation | alephsysno: 002331037, proquestno: AAINR25171, Theses scanned by UMI/ProQuest. |
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