We are studying the structure-function relationships of chemokines and their receptors. We have identified an indirect pathway by which IL-8 attracts mononuclear cells by the process of neutrophil degranulation. This results in the release of defensins 1 and 2 and CAP37/azurocidin which are T-cell chemoattractants and the monocyte chemoattractant, cathepsin G. The biological relevance of these in vitro results were reinforced by observations that subcutaneous injections of defensins, cathepsin G or azurocidin result in the local accumulation of inflammatory cells. Furthermore, we have found that defensins and cathepsin G each have adjuvant activities and enhance in vivo antibody responses. We are currently identifying the receptor (s) for cathepsin G. A major goals of these studies is to ascertain whether these neutrophil granule products mediate the capacity of neutrophils to activate mononuclear cell responses. The proinflammatory and potential tumor promoting effects of chemokines points to the need to develop potent inhibitors. We are approaching this by studying the molecular mechanisms of desensitization of chemokine responses. We have initiated studies of heterologous desensitization of chemokines receptors by opioids. Opioids also utilize seven transmembrane receptors (STM) and are chemotactic. Prior exposure to metenkephalin can cross-phosphorylate and block subsequent monocyte and neutrophil chemotactic responses to chemokines. This may account for anti-inflammatory effects of opioids. Furthermore, we have documented that gp120 and gp41 from various strains of HIV-1 can down-regulate and internalize a number of the chemokine receptors as well as the FMLP receptor. As a result, human monocytes and T cells, have reduced chemotactic responses to these stimuli, suggesting that HIV-1 envelope proteins disarm host inflammatory responses by this pathway. Based on the report that some C-C chemokines can interfere with invasion of cells via chemokine coreceptors, we established that a distamycin analogue known to prevent HIV-1 cell entry dies so by selectively interfering with ligand-receptor interaction of CCR5 and CXCR4. AIDS TITLE: Role of chemokines in resistance to HIV-1.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC009369-07
Application #
6161080
Study Section
Special Emphasis Panel (LMI)
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
1997
Total Cost
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
de la Rosa, Gonzalo; Yang, De; Tewary, Poonam et al. (2008) Lactoferrin acts as an alarmin to promote the recruitment and activation of APCs and antigen-specific immune responses. J Immunol 180:6868-76
Wang, Zhao Yuan; Yang, De; Chen, Qian et al. (2006) Induction of dendritic cell maturation by pertussis toxin and its B subunit differentially initiate Toll-like receptor 4-dependent signal transduction pathways. Exp Hematol 34:1115-24
Zhang, Ning; Yang, De; Dong, Huifang et al. (2006) Adenosine A2a receptors induce heterologous desensitization of chemokine receptors. Blood 108:38-44
Hu, Paul Q; Oppenheim, Joost J; Medsger Jr, Thomas A et al. (2006) T cell lines from systemic sclerosis patients and healthy controls recognize multiple epitopes on DNA topoisomerase I. J Autoimmun 26:258-67
Krakauer, Teresa; Chen, Xin; Howard, O M Zack et al. (2005) Triptolide attenuates endotoxin- and staphylococcal exotoxin-induced T-cell proliferation and production of cytokines and chemokines. Immunopharmacol Immunotoxicol 27:53-66
Kurosaka, Kahori; Chen, Qian; Yarovinsky, Felix et al. (2005) Mouse cathelin-related antimicrobial peptide chemoattracts leukocytes using formyl peptide receptor-like 1/mouse formyl peptide receptor-like 2 as the receptor and acts as an immune adjuvant. J Immunol 174:6257-65
Howard, O M Zack; Dong, Hui Fang; Su, Shao Bo et al. (2005) Autoantigens signal through chemokine receptors: uveitis antigens induce CXCR3- and CXCR5-expressing lymphocytes and immature dendritic cells to migrate. Blood 105:4207-14
Chen, Xin; Murakami, Takaya; Oppenheim, Joost J et al. (2005) Triptolide, a constituent of immunosuppressive Chinese herbal medicine, is a potent suppressor of dendritic-cell maturation and trafficking. Blood 106:2409-16
Carlos, Casey A; Dong, Hui Fang; Howard, O M Zack et al. (2005) Human tumor antigen MUC1 is chemotactic for immature dendritic cells and elicits maturation but does not promote Th1 type immunity. J Immunol 175:1628-35
Oppenheim, Joost J; Dong, Hui Fang; Plotz, Paul et al. (2005) Autoantigens act as tissue-specific chemoattractants. J Leukoc Biol 77:854-61

Showing the most recent 10 out of 52 publications