Grant Number :    1Z01BC009369-11

Pricipal Investigator : Oppenheim Joost

Project Title : Consequences of Chemokine-Receptor Interactions

Abstract : We have further pursued our studies showing that antimicrobial peptides involved in innate host defense also interact with receptors on host inflammatory cells resulting in adaptive immune responses. Human granulocyte derived -defensins are chemotactic for resting naive T cells and immature dendritic cells. The physiological relevance of these findings were documented by showing that the -defensins when coadministered in a vaccine act as potent immunoadjuvant that enhance the humoral as well as cellular immune response even to relatively weak idiotypic tumor antigens from a B cell lymphoma. In collaboration with NCI biophysicists led by Dr. Jacek Lubkowski, the epithelial cell derived -defensins which are chemotactic for immature dendritic cells and resting memory cells that express the CCR6 receptor for "LARC", were shown to have a tertiary structure resembling that of chemokines. Drs. De Yang and Oleg Chertov in our laboratory extended these findings to show that cathelicidin (LL37) another antimicrobial product of both neutrophils and epithelial cells can also mobilize leukocytes engaged in host defense by interacting with the FPRL-1 receptor. Furthermore the expression of classical chemoattractant receptors such as C5a, FPR and FPRL-1 on immature and mature dendritic cells has been demonstrated to further understand their role in the processing and delivery of antigen to T cells to help initiate immune responses. Dr. Oleg Chertov has identified cathepsin G released by neutrophils in the course of degranulation as a chemoattractant of phagocytes and as a vaccine immunoadjuvant if administered together with antigens. We have studied of the role of chemokines in angiogenesis and their contribution to tumor progression. Dr. Rosalba Salcedo showed that human microvascular endothelial cells (HMVEC) express more functional chemokines receptors than the less mature human umbilical vein endothelial cells (HUVEC). This enabled her to show that HMVEC express functional CCR2 and CCR3 as well as CXCR1-3 and react to chemokine ligands such as MCP-1 and Eotaxin. These ligands also have in vivo angiogenic activities in a matrigel plug assay. We previously reported that prior exposure to opiates such as endorphins and morphine by interacting with m,d and k opioid (GPCR) receptors can heterologously desensitize and phosphorylate a number of chemokine receptors, making them temporarily unresponsive to these chemokines. In collaboration with Dr. Tom Rogers we can show that this is a bidirectional process. Prior exposure to a number of chemokines results in the desensitization and phosphoylation of the opioid mu receptor. This may provide another mechanisms by which the pair signals from inflammatory sites are accentuated by suppression of the opioid signals. Analyses of components in Chinese herbal medicines and extracts of plants with purported anti-inflammatory properties available in the National Product Repository of the NCI have led us to identify a number of molecular entities that inhibit the chemotactic activities of a number of proinflammatory chemokines. Chenodeoxycholic acid (CDCA) to a lesser degree deoxyoxycholic acid (CDA) at nontoxic concentrations selectively inhibit ligands interacting with FPR and FPRL-1. However, these agents are also known to interact with nuclear receptors and therefore suppress cytokine production and immune responses. These agents consequently also have anti-angiogenic effects and we are investigating their effects on in vivo tumor growth in SCID mice. In collaboration with Dr. M. Cushman at Indiana University we have shown that cosalane compounds interfere with RANTES capacity to interact with CCR1 receptors. These compounds also have anti-angiogenic effects and are being tested on human tumor models in SCID mice. Another component in Chinese anti-inflammatory medicinals known as shikonin was found to selectively interfere with CCR1-ligand interactions. However, it also blocks the chemotactic effect of all chemokines by interfering with GPCR initiated signal transduction. We are at present studying the mechanism of action of this potentially potent anti-inflammatory and anti angiogenic agent.

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