INTERLEUKIN-8 RECEPTORS R1 AND R2 ACTIVATE MITOGEN-ACTIVATED PROTEIN-KINASES AND INDUCE C-FOS, INDEPENDENT OF RAS AND RAF-1 IN CHINESE-HAMSTER OVARY CELLS

Many of the biological effects of interleukin-8 (IL-8) are realized by binding to the two seven-transmembrane receptors IL-8 R1 and IL-8 R2. IL-8 Ri is activated only by IL-8, while IL-8 R2 is activated by IL-8 , GRO alpha, and a few other cr chemokines. In addition to the well-kn own chemoattractant function, IL-8 is also angiogenic and mitogenic. I L-8 R1 and R2 have been shown to interact with G alpha(i2) and G alpha (16), resulting in the activation of several mitogen-activated protein kinases. We have investigated IL-8 R1 and IL-8 R2 regulated upstream mediators and downstream effects of extracellularly responsive kinase (ERK) signaling pathways by expressing the individual receptors in a h eterologous system. Our results demonstrate the following in CHO cells stably expressing either IL-8 R1 or R2 receptors: (a)IL-8 activates E RK and ERK kinases (MEK) through R1. Both IL-8 and GRO alpha activate ERK and MEK through R2, whereas MIP-1 alpha, a beta chemokine, does no t activate these kinases through either of these receptors. (b) ERK ac tivation is inhibited by pertussis toxin and MEK1 inhibitor. (c) ERK a ctivation is independent of the upstream mediators Ras and Raf-1. (d) The downstream effects of ERK activation result in an increase of c-fo s mRNA through both R1 and R2 receptors.