The role of TPL2 in the pathogenesis of idiopathic pulmonary fibrosis

Postgraduate Thesis uoadl:1936786 751 Read counter

Unit:
Κατεύθυνση Κλινική Βιοχημεία - Μοριακή Διαγνωστική
Library of the School of Science
Deposit date:
2017-09-30
Year:
2017
Author:
Grigorakaki Theodora
Supervisors info:
Ευρύκλεια Λιανίδου, Καθηγήτρια Αναλυτικής Χημείας-Κλινικής Χημείας, Τμήμα Χημείας, Εθνικό Καποδιστριακό Πανεπιστήμιο Αθηνών
Βασίλης Αϊδίνης. Ερευνητής Α΄, Εργαστήριο Ανοσολογίας, Ερευνητικό Κέντρο Βιοϊατρικών Επιστημών (ΕΚΕΒΕ) «ΑΛΕΞΑΝΔΡΟΣ ΦΛΕΜΙΝΓΚ».
Original Title:
ΜΕΛΕΤΗ ΤΟΥ ΡΟΛΟΥ ΤΟΥ ΓΟΝΙΔΙΟΥ TPL2 ΣΤΗΝ ΠΑΘΟΓΕΝΕΙΑ ΤΗΣ ΙΔΙΟΠΑΘΟΥΣ ΠΝΕΥΜΟΝΙΚΗΣ ΙΝΩΣΗΣ
Languages:
Greek
Translated title:
The role of TPL2 in the pathogenesis of idiopathic pulmonary fibrosis
Summary:
The aberrations are pleiotropic, but mitogen‐activated protein kinase (MAPK) pathways feature prominently. Tpl2/COT is a serine‐threonine MAPK kinase (MAP3K8) at the crossroad of various signal transduction pathways that control fundamental cellular processes such as growth, proliferation, differentiation, migration and apoptosis. Specifically, Tpl2 kinase (or MAP3K8) induces T-lymphoblastic lymphoma growth when expressed in transgenic mice rearranged (truncated) at its C-terminus, while overexpression of the wild type protein is also oncogenic. In humans it has been implicated in Hodgkin’s lymphoma, in nasopharyngeal cancer and breast cancer. Recently a 3’ end mutation was discovered in lung cancer. Its normal function includes participation in T lymphocyte activation and IL-2 production. It is inhibitory for the cell-cycle regulatory protein p27kip and induces various transcription factors that stimulate cytokine production like IL-2 and promote cell proliferation. Moreover it participates in TNF-α production from macrophages as well as TNF-α and CD40 signaling in macrophages and B-lymphocytes. The truncated kinase seems to be more potent. Despite early studies identifying the importance of Tpl2 as a downstream mediator of LPS/TLR4 signaling and evidence in the literature for functions of ERK in fibrosis, it was determined thatTpl2 regulates the expression of genes regulating fibrogenic processes in the liver. As a proto‐oncogene activated by C‐terminal truncation in mouse and rat, a detailed evaluation of its expression and function in human malignancy is missing and the physiological role of Tpl2/COT in fibrogenesis remains enigmatic. One of the three major human tissues where Tpl2 is expressed at highest levels is the lung. Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults and characterized by a progressive worsening of lung function and a poor prognosis. To date, no management approach has proven efficacious. The aim of the present study was on the characterization of the role and of the mechanisms regulating the expression of Tpl2 in the IPF development. In this regard, we were able to reveal an unprecedented role for Tpl2 as suppressor of IPF its expression in fibrotic lungs in the animal model, and found it to be down-regulated. Testing several target molecules within 15 available datasets available from Gene Expression Omnibus (GEO) and EMBL-EBI Array Express data repositories we found that MAP3K8/TPL2 specifically was downregulated upon IPF, NSIP and Scleroderma consistently in several datasets tested.or META analysis on Genome Wide expression profiles revealed MAP3K8 consistently downregulated in idiopathic interstitial pneumonias (IIPs) patient datasets. This is supported by our in vivo experimental data showing that ablation of the Tpl2 gene in mice dramatically accelerates the onset and multiplicity of BLM ‐induced lung fibrosis. Tpl2-deficient mice exhibit significant differences in following BLM administration compared with wild-type mice. To examine the cellular basis of the fibrosis-suppressive role of Tpl2, we used lysozyme-Cre (LysM-Cre) mice, conferred a similar susceptibility to IPF development. To examine whether TPL2 functions in hematopoietic cells or the radioresistant nonhematopoietic cells, we generated bone marrow–chimeric mice by adoptively transferring Tpl2+/+ or Tpl2-/- bone marrow cells into lethal dose–irradiated Tpl2+/+ recipient mice. When reconstituted with either the Tpl2+/+ bone marrow or the Tpl2-/- bone marrow, the recipient mice were competent in IPF induction. As a complementary approach, we adoptively transferred Tpl2+/+ bone marrow into lethal dose–irradiated Tpl2+/+ or Tpl2-/- mice. The results showed that if Tpl2 is disrupted only in hematopoietic cells, its ablation is significant sufficient to induce the IPF enhancement phenotype. To determine whether Tpl2 controls the induction of COX-2, we measured COX-2 mRNA expression/ levels of COX-2 RNA in lungs tissue of Tpl2+/+ and Tpl2–/– mice. The results showed that COX-2 induction is significantly lower in Tpl2–/– mice. To assess in vivo the physiological significance of Cox-2-PGE2 activation through Tpl2, we treated Tpl2-/- and Tpl2+/+ mice concurrently with bleomycin and 16,16-dimethyl PGE2(dmPGE2), a stable analog of endogenous PGE2, or with saline as a control. Exogenous PGE2 administration rescues mice with complete or Tpl2 ablation from defects in lung function and susceptibility to fibrosis. Collectively, these observations provide evidence that Tpl2 has a critical prophylactic role in the susceptibility to pulmonary fibrosis.
Main subject category:
Science
Keywords:
idiopathic, pulmonary, fibrosis
Index:
Yes
Number of index pages:
3
Contains images:
Yes
Number of references:
105
Number of pages:
149
ΜΕΛΕΤΗ ΤΟΥ ΡΟΛΟΥ ΤΟΥ ΓΟΝΙΔΙΟΥ TPL2 ΣΤΗΝ ΠΑΘΟΓΕΝΕΙΑ ΤΗΣ ΙΔΙΟΠΑΘΟΥΣ ΠΝΕΥΜΟΝΙΚΗΣ ΙΝΩΣΗΣ .pdf (3 MB) Open in new window