טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentMessika Orit
SubjectModulation of the Matrix-Metalloproteinase (MMPS) in B-cell
lymphopoiesis
DepartmentDepartment of Medicine
Supervisors Professor Ariel Miller
Professor Doron Melamed


Abstract

The Matrix-Metalloproteinases (MMPs) are proteolitic enzymes that degrade the extracellular matrix (ECM), thus involved in cellular migration. The MMPs play an important role in physiological and pathological inflammatory processes. Preliminary studies have shown that human mature B cell lines produce MMPs, and that this production is modulated in response to mitogens and cytokines. We investigated the secretion of MMP-9 during B- lymphopoiesis, and its modulation in response to different mitogens and cytokines. To do so, we used our bone marrow culture system and well-studied mutated mouse models to prepare the different B cell populations. Our results show that MMP-9 is consistently secreted throughout B lymphopoiesis, and that the level of secreted MMP-9 is developmentally regulated. High level of MMP-9 is spontaneously produced in early stages of B cell development, prior to B cell receptor (BCR) expression (ProB and PreB), which drops at the later stages of development (Immature B, Transitional B and Mature B). Using RT-PCR we found that interferon (IFN)-beta receptor is produced throughout B cell development, while tumor necrosis factor (TNF)-alpha receptor (p55) and IFN-gamma receptor expression is initiated only at the preB stage. We found that TNF-alpha stimulates MMP-9 secretion in transitional cells whereas IFNs suppress MMP-9 secretion in immature cells. In response to mitogens, we found that LPS and PMA suppressed MMP-9 secretion in transitional cells, whereas LPS and ConA stimulated MMP-9 secretion in mature B cells. We conclude that B lymphocyte development is accompanied with MMP-9 secretion and the developing cells are competent to modify this secretion upon different immune stimuli. These finding may have implications in physiological aspects of developmental immunology, as well as to B cell migration in pathological processes such as lymphoprolopherative and autoimmune B cell disorders.