Regulated Secretion of Chemokines from Endothelial Cells pp. 155-175
Authors: Inger Oynebraten, Guttorm Haraldsen, University of Oslo, Norway
Abstract: Circulating leukocytes interact with endothelial cells (ECs) via selectins until being activated by chemokines that enable the firm, integrin-mediated adhesion required for subsequent transmigration. We observed that the prototype chemokine IL-8 (CXCL8) localizes similar to P-selectin in the Weibel-Palade body (WPB) of vascular ECs, and that exposure to histamine or thrombin leads to exocytosis of IL-8 within minutes (i.e. regulated secretion) [1,2]. Subsequent studies allowed us to demonstrate that chemokines produced by the endothelium can be classified into three groups, i) those that are limited to constitutive secretion (IP-10 (CXCL10) and RANTES (CCL5)) , ii) those that are released by regulated secretion from a dense secretory granule, the WPB (IL-8 and eotaxin-3 (CCL26)) [1-3], and iii) those that are released by regulated secretion from small granules (GRO (CXCL1) and MCP-1 (CCL2)) [3,4]. These latter granules are more sensitive to modulators of protein kinase A and C compared to the WPB and represent a new compartment that might enable differential chemokine release from ECs in response to currently unknown extracellular cues . Signals or domains that target chemokines to compartments of regulated secretion in ECs are currently unknown and sorting of RANTES to granules of T cells and platelets [5,6] but not to such compartments in ECs implies cell-type specific mechanisms. Taken together, the secretory pathway of ECs seems to harbour highly controlled mechanisms for chemokine secretion to the cell exterior which might be important to fine tune leukocyte extravasation. Moreover, our data imply that regulated secretion of chemokines from the endothelium is restricted to those that predominantly recruit leukocytes of the innate immune system. In this manner, regulated chemokine secretion might enhance rapid recruitment of leukocytes involved in the first line of defense to sites of inflammation.