טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentTamir Ronit-Rachel
SubjectSignal Transduction Pathways and Secretory Effector
Functions Mediated by IL-16 Stimulation of
Monocyte/Macrophages
DepartmentDepartment of Medicine
Supervisor Professor Shimon Pollack


Abstract

Interleukin 16(IL-16) has been characterized as a chemoattractant for a variety of CD4+ immune cells: lymphocytes, monocytes, eosinophils and dendritic cells. Following binding to the CD4 receptor on lymphocytes, IL-16 stimulation results in activation and autophosphorylation of p56lck, a Src family protein tyrosine kinase(PTK), that is associated with the cytoplasmaic tail of CD4. Hck, which is a member of the Src family, has been shown to be a critical component in the signal transduction pathway of several monocyte/macrophage-activating factors. Since monocytes lack the p56lck, Hck activation, by association with the intracytoplasmic tail of CD4, could be involved in the mediation of monocyte responses to IL-16. The activation of the MAPK family of kinases(ERK,JNK and p38) is often initiated by proximal activation of PTKs.
In view of these findings, we decided to investigate the involvement of Hck and MAPK pathways in the signaling cascade initiated by IL-16 in monocyte/macrophages and to test the effector functions induced by IL-16 stimulation.
We have shown that IL-16 stimulation of PMA-MΦ (differentiated THP-1 human monocytes) involves the activation and the phosphorylation of Hck and the MAPK enzymes ERK, JNK and p38. CD4 molecule is required to elicit IL-16-induced cell signaling in PMA-MΦ, and the resulting MAPK phosphorylation is dependent on Hck activation. IL-16 stimulation of PMA-MΦ results also in selective secretion of certain chemokines( MCP-1, RANTES and MIP-3α) and the cytokine IL-10. The secretion of MCP-1, RANTES and IL-10 is associated with Hck and MAPK activation whereas MIP-3α secretion might be associated with some other signal transduction pathways induced by IL-16. Our findings suggest that IL-16, except of being a direct chemoattractant on CD4+ inflammatory cells, may augment its chemotactic activity by the induction of the secretion of chemokines, which affect also CD4-negative inflammatory cells.