Role of interleukin-8 monomer-dimer equilibrium and glycosaminoglycan interactions in neutrophil recruitment

Chemokines are small, soluble secreted proteins that induce cell migration through activation of G Protein Coupled Receptors (GPCR), and also bind extracellular matrix\r\nglycosaminoglycans (GAG) for recruiting target cells. Interleukin-8 (IL-8) is a proinflammatory chemokine, recruits neutrophils as a host response to infection and tissue injury.. An imbalance in the recruitment process has been attributed to a variety of autoimmune and inflammatory diseases. Knowledge of in vivo IL-8„ŸGAG interactions is one of the first steps towards understanding the in vivo physiology and molecular mechanisms regulating neutrophil recruitment. All chemokines including IL-8 exist as both monomers and dimers and in vitro studies have shown that both monomers and dimers of IL-8 can bind to GPCRs and GAGs, though with different affinities and specificities. However, the role of monomers, and dimers and of monomer-dimer equilibrium in regulating in vivo IL-8 function is not known. We hypothesize that the dynamic equilibrium between monomers and dimers in solution and in GAG-bound form is essential for regulation of in vivo neutrophil recruitment. Studying the role of monomers and dimers in isolation is experimentally challenging, as the monomers and dimers exist in equilibrium. This equilibrium prevents studying one species without interference from the other. We used an innovative approach, where we have used obligate monomers and obligate dimers to overcome this hurdle, and have studied the role of monomer-dimer equilibrium and GAG-binding in neutrophil recruitment. The knowledge from this study could provide valuable information for the inhibition of chemokine function, and be used for designing drugs for inflammatory and autoimmune diseases.\r\n

Name thesis:degree_name

Master of Science

Level thesis:degree_level

Master

Grantor

The University of Texas Medical Branch

Year dc:date.issued

2008

Author dc:creator

• Pavani Kumari Gangavarapu

Advisor dc:contributor.advisor

• Dr. Sarita Sastry

Committee members dc:contributor.committeemember

• Dr. Roberto Garofalo
• Dr. Krishna Rajarathnam

• Interleukin-8
• glycosaminoglycan
• chemokines

Statement dc:rights

• Copyright © is held by the author. Presentation of this material on the TDL web site by The University of Texas Medical Branch at Galveston was made possible under a limited license grant from the author who has retained all copyrights in the works.

Language dc:language.iso

eng

Dc Identifier Other

etd-08252008-100443

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/216