Mechanisms of inflammatory cytokine secretion by mast cells.
Date
1999
Authors
Zhu, Fu-Gang.
Journal Title
Journal ISSN
Volume Title
Publisher
Dalhousie University
Abstract
Description
Mast cells are major effector cells in the immune system, notable for their key roles in allergic diseases and innate defense against bacterial infections. Cytokines are major tools, through which mast cells exert their functions. In the studies described in the present thesis we have sought to elucidate mechanisms of inflammatory cytokine secretion by murine bone marrow derived mast cells (mBMMC) and KU812, a human cell line with both basophilic and mast cell features after differentiation in culture.
We have demonstrated that IL-6 and GM-CSF secretion by both mBMMC and differentiated KU812 cells is almost exclusively through a vesicular transport dependent pathway, and that ionophore induced short-term release of IL-6 by differentiated KU812 cells is not primarily due to degranulation. We have also demonstrated that bacterial DNA and oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG-ODN) activate mBMMC and differentiated KU812 cells. CpG-ODN, but not control oligodeoxynucleotides without CpG motifs, induced a dose dependent increase in production of both IL-6 and TNF-alpha by mBMMC. Bacterial DNA, but not calf thymus DNA, also induced IL-6 production from both mBMMC and KU812 cells. Our studies have therefore demonstrated the major secretion pathway for IL-6 and GM-CSF in mBMMC and differentiated KU812 cells, and also identified CpG-ODN and bacterial DNA as novel stimuli for cytokine induction in mast cells. The results described in this thesis have important implications for our understanding of the mechanisms by which mast cells function in host defense and inflammation.
Thesis (Ph.D.)--Dalhousie University (Canada), 1999.
We have demonstrated that IL-6 and GM-CSF secretion by both mBMMC and differentiated KU812 cells is almost exclusively through a vesicular transport dependent pathway, and that ionophore induced short-term release of IL-6 by differentiated KU812 cells is not primarily due to degranulation. We have also demonstrated that bacterial DNA and oligodeoxynucleotides containing immunostimulatory CpG motifs (CpG-ODN) activate mBMMC and differentiated KU812 cells. CpG-ODN, but not control oligodeoxynucleotides without CpG motifs, induced a dose dependent increase in production of both IL-6 and TNF-alpha by mBMMC. Bacterial DNA, but not calf thymus DNA, also induced IL-6 production from both mBMMC and KU812 cells. Our studies have therefore demonstrated the major secretion pathway for IL-6 and GM-CSF in mBMMC and differentiated KU812 cells, and also identified CpG-ODN and bacterial DNA as novel stimuli for cytokine induction in mast cells. The results described in this thesis have important implications for our understanding of the mechanisms by which mast cells function in host defense and inflammation.
Thesis (Ph.D.)--Dalhousie University (Canada), 1999.
Keywords
Health Sciences, Immunology.