In this study, we examined how IL-8 induces leukocyte migration on major beta 1 integrin ligands derived from the extracellular matrix protein fibronectin. We assessed individual contributions of signaling by IL-8 receptors by transfection of CXCRI and CXCR2 into rat basophilic leukemia (RBL) cells and human monocytic THP-1 cells. CXCRI expressing cells migrated on the fibronectin ligands for alpha 4p1 and alpha 5 beta 1 integrins in response to IL-8, whereas CXCR2 expressing cells did not. RBL cells expressing the chimeric CXCR1 receptor containing the cytoplasmic tail of CXCR2 had greatly blunted migration, whil,2 cells expressing the CXCR2 chimera with the tail of CXCRI had augmented migration. Last, inhibitors of p38 and JNK MAP kinases blocked IL-8-indUced migration in CXCR 1(+) cells. We conclude that IL-8 stimulated beta 1 integrin-mediated leukocyte migration on fibronectin through CXCRI is dependent on the C-terminal cytoplasmic domain of CXCRI and subsequent p38 and JNK MAPK signaling. (c) 2005 Elsevier Inc. All rights reserved.