Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases

Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases

^*Division of Basic Sciences, Department of Pediatrics, ^†Program in Molecular Signal Transduction, and ^§Department of Medicine, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206; and Departments of ^¶Medicine and ^‖Pharmacology, University of Colorado Health Sciences Center, Denver, CO 80262

Abstract

Chemoattractants and chemokines, such as interleukin 8 (IL-8), are defined by their ability to induce directed cell migration of responsive cells. The signal transduction pathway(s) leading to cell migration remain ill defined. We demonstrate that phosphatidylinositol-3-kinase (PI3K) activity, as determined by inhibition using wortmannin and LY294002, is required for IL-8-induced cell migration of human neutrophils. Recently we reported that IL-8 caused the activation of the Ras/Raf/extracellular signal-regulated kinase (ERK) pathway in human neutrophils and that this activation was dependent on PI3K activity. The regulation of cell migration by IL-8 is independent of ERK kinase and ERK activation since the ERK kinase inhibitor PD098059 had no effect on IL-8-induced cell migration of human neutrophils. Additionally, activation of p38-mitogen-activated protein kinase is insufficient and activation of c-Jun N-terminal kinase is unnecessary to induce cell migration of human neutrophils. Therefore, regulation of neutrophil migration appears to be largely independent of the activation of the mitogen-activated protein kinases. The data argue that PI3K activity plays a central role in multiple signal transduction pathways within the human neutrophil leading to distinct cell functions.

Footnotes

↵ ‡ To whom reprint requests should be addressed.
Philippa Marrack, National Jewish Medical and Research Center, Denver, CO
ABBREVIATIONS:

PI3K,

phosphatidylinositol-3-kinase;

IL-8,

interleukin 8;

ERK,

extracellular signal-regulated kinase;

MEK,

ERK kinase;

MAPK,

mitogen-activated protein kinase;

JNK,

c-Jun N-terminal kinase;

TNF-α,

tumor necrosis factor α;

KRPD-HSA,

Krebs–Ringer phosphate buffer containing dextrose and human serum albumin