Characterization of ERK Activation in Human Mast Cells Stimulated by Contact with T Cells
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Characterization of ERK Activation in Human Mast Cells Stimulated by Contact with T Cells Adam Mor,1,2,3,4,5 Irit Shefler,1,2 Pazit Salamon,1,2 Yoel Kloog,3 and Yoseph A. Mekori1,2
Abstract—Close physical proximity between mast cells and T cells has been demonstrated in several human conditions. We have identified and characterized a novel mast cell activation pathway initiated by contact with T cells, and showed that this pathway is associated with cytokine release. It has been shown recently that Ras is activated in this pathway. Thus, in the present study we further explore the downstream events associated with Ras activation and cytokine release in human mast cells stimulated by contact with T cells. ERK activation in human mast cells stimulated by either contact with T cells or by crosslinking the FC epsilon receptor was studied. Photobleaching experiments were used to study ERK localization. Enzyme linked immunosorbent assay was used to study the cytokine release by human mast cells. We show that stimulation of human mast cells by contact with activated T cells results is sustained ERK activation. Furthermore, sustained ERK activation in these cells is associated with increased dwell time at the nucleus and with IL-8 release. Interestingly, when mast cells were stimulated by crosslinking the FC epsilon receptor I, ERK activation was transient. ERK activation was associated with a shorter dwell time at the nucleus and with TNF-α release. Thus, retaining ERK in the nucleus might be a mechanism utilized by human mast cells to generate different cytokines from a single signaling cascade. KEY WORDS: mast cells; T cells; ERK; IL-8.
interaction between these cells is bidirectional. We have recently identified and characterized a novel MC activation pathway initiated by contact with activated T cells or their membranes and showed that this pathway is associated with cytokine release [2, 3]. More recently, we studied the spatiotemporal pattern of Ras (Harvey rat sarcoma viral oncogene) activation in this pathway [4]. We showed that Ras is activated at the plasma membrane and at the Golgi apparatus of MC stimulated by contact with activated T cells and that this pattern of activation is RasGRP1 dependent. In the present study, we further explore and characterize the downstream events associated with Ras activation and suggest a possible mechanism that might control extracellular signal regulated kinase (ERK) activation and MC interleukin (IL)-8 and tumor necrosis factor (TNF)-α release.
INTRODUCTION Close physical proximity between mast cells (MC) and T cells has been demonstrated in several human conditions such as sarcoidosis, rheumatoid arthritis, and inflammatory bowel disease [1]. It is well known that MC are capable of activating T cells. Apparently, the
Yoel Kloog and Yoseph A. Mekori contributed equally to this work. 1
The Laboratory of Allergy and Clinical Immunology, Meir Medical Center, Kfar Saba, Israel 2 Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 3 Department of Neurobiology, The Geor
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