IL-8 is a chemokine produced during the inflammatory response. It has been detected in acute and chronic inflammatory diseases including acute respiratory distress syndrome, cystic fibrosis, chronic bronchitis and rheumatoid arthritis. The evidence is increasing that IL-8 is not only present, but a major causative agent for leukocyte infiltration during the inflammatory response. Because IL-8 attracts PMNs into an area of inflammation, it becomes important to understand how IL-8 interacts with its two neutrophilic receptors on the molecular level. Clear definition of the receptor and ligand structures that account for high affinity binding of IL-8 is necessary. More than one region on IL-8 appears to bind to each of the two receptors which should be reflected in more than one binding site on each receptor. In order to define the sites on the IL-8 A and B receptors that are involved in high affinity ligand binding, mutated receptor constructs - both loop exchange and selected point mutations - will be assessed for their ligand binding affinity and their functional capacity following transfection into HL60 cells. The combination of these studies with ongoing studies on IL-8 itself should provide clear definition of the complex interaction of IL-8 with its two receptors. This analysis will shed light on the field of receptor structure/function. Eventually knowledge of these specific sites of ligand/receptor interaction will provide a foundation for rationale approaches to develop inhibitory reagents by developing steric mimics of these regions. In the meantime antibodies have been produced to rabbit IL-8 A and B receptors that block IL-8 interaction with both receptors. These will be used to evaluate the role of IL-8 in leukocyte participation in a rabbit model of pulmonary inflammation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL055657-04
Application #
6074387
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1996-07-01
Project End
2000-06-30
Budget Start
1999-02-01
Budget End
1999-06-30
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
La Jolla Institute
Department
Type
DUNS #
941462285
City
San Diego
State
CA
Country
United States
Zip Code
92121
Wimmer, Antonia; Khaldoyanidi, Sophia K; Judex, Martin et al. (2006) CCL18/PARC stimulates hematopoiesis in long-term bone marrow cultures indirectly through its effect on monocytes. Blood 108:3722-9
DiScipio, Richard G; Schraufstatter, Ingrid U; Sikora, Lyudmila et al. (2006) C5a mediates secretion and activation of matrix metalloproteinase 9 from human eosinophils and neutrophils. Int Immunopharmacol 6:1109-18
Zhao, Ming; Discipio, Richard G; Wimmer, Antonia G et al. (2006) Regulation of CXCR4-mediated nuclear translocation of extracellular signal-related kinases 1 and 2. Mol Pharmacol 69:66-75
Burger, Meike; Hartmann, Tanja; Burger, Jan A et al. (2005) KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway. Oncogene 24:2067-75
Liu-Bryan, Ru; Pay, Salih; Schraufstatter, Ingrid U et al. (2005) The CXCR1 tail mediates beta1 integrin-dependent cell migration via MAP kinase signaling. Biochem Biophys Res Commun 332:117-25
Schraufstatter, Ingrid; Takamori, Hiroshi; Sikora, Lyudmila et al. (2004) Eosinophils and monocytes produce pulmonary and activation-regulated chemokine, which activates cultured monocytes/macrophages. Am J Physiol Lung Cell Mol Physiol 286:L494-501
Zhao, Ming; Wimmer, Antonia; Trieu, Khanh et al. (2004) Arrestin regulates MAPK activation and prevents NADPH oxidase-dependent death of cells expressing CXCR2. J Biol Chem 279:49259-67
Schraufstatter, Ingrid U; Trieu, Khanh; Zhao, Ming et al. (2003) IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor. J Immunol 171:6714-22
Schraufstatter, Ingrid U; Trieu, Khanh; Sikora, Lyudmila et al. (2002) Complement c3a and c5a induce different signal transduction cascades in endothelial cells. J Immunol 169:2102-10
Schraufstatter, I U; Chung, J; Burger, M (2001) IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways. Am J Physiol Lung Cell Mol Physiol 280:L1094-103

Showing the most recent 10 out of 13 publications