The responses of CysLT receptor have been reported to be

The responses of CysLT2 receptor have been reported to be related to several isolated signaling events, such as induction of early growth response-1 (Egr-1) (Uzonyi et al., 2006), eliciting β-arrestin-2 binding (Yan et al. (2011)), production of inositol phosphates and phosphorylation of NF-κB p65 (Brochu-Bourque et al., 2011), and phosphorylation of JUN, ERK and p38 (Brochu-Bourque et al., 2011, Qi et al., 2011). In human umbilical vein Myosmine sale (HUVECs), LTD4 induces synthesis of Egr-1, a transcriptional factor localized in the nucleus, and promotes interleukin-8 (IL-8) synthesis and secretion (Uzonyi et al., 2006). This finding suggests one of the possible signaling pathways of CysLT2 receptors, i.e. Egr-1 may be involved in CysLT2 receptor-mediated IL-8 production; however, the details remain to be clarified. In another study, LTC4via the CysLT2 receptor transcriptionally activates IL-8 production through induction of NF-κB and AP-1 transcription factors, namely the PKCɛ/NF-κB and PKCδ/AP-1 pathways (Thompson et al., 2008). Also, LTD4-induced IL-8 promoter activity is a CysLT2 receptor response in HEK293 cells expressing wild-type or M201V mutant CysLT2 receptors, which is associated with phosphorylation of the mitogen-activated protein kinases (MAPKs) ERK1/2, JUN and p38 (Brochu-Bourque et al., 2011). In these studies, the inflammatory cytokine IL-8 was demonstrated as one of the responsible molecules induced by CysLTs via activating CysLT2 receptors. IL-8 is synthesized in and released from mononuclear cells, macrophages, fibroblasts and airway epithelial cells, and it promotes inflammation as a potent chemoattractant factor (Baggiolini et al., 1995, Nakamura et al., 1991, Rolfe et al., 1991) in recruitment and activation of polymorphonuclear cells (Harada et al., 1994). The IL-8 synthesis is transcriptionally regulated by several signal pathways including the Egr-1 pathway (Moon et al., 2007a). Egr-1 (also known as krox24, zif268, NGFU-A and TIS-8) can be immediately induced after acute cell injury (Braddock, 2001). Its expression is modulated by extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) (Moon et al., 2007a). The protein product of Egr-1 is a transcriptional factor with a Cys2-His2-typed zinc-finger, binding with “GC” in the DNA regulatory element (Christy and Nathans, 1989, Lemaire et al., 1988, Lim et al., 1987, Milbrandt, 1987). It regulates expression of target genes associated with inflammation, differentiation, growth and development (Khachigian and Collins, 1997). In the kidneys and lungs, or in the early systemic inflammatory responses in endotoxemic mice, Egr-1 does not contribute to the early inflammatory response, but to the sustained expression of inflammatory mediators (Pawlinski et al., 2003). Although the CysLT2 receptor has been reported to mediate LTC4-induced up-regulation of IL-8 by the transcriptional factors NF-κB and AP-1, the role of the Egr-1 pathway remains unknown. Thus, in the present study we investigated the regulation of IL-8 production by the CysLT2 receptor through the ERK1/2-Egr-1 pathway in human embryonic kidney 293 (HEK293) cells transfected with the receptor genes.