Our Science – Oppenheim Website
Joost J. Oppenheim, M.D.
Deputy Director, Cancer Inflammation Program
Chief, Laboratory of Molecular Immunoregulation
Dr. Oppenheim obtained his M.D. degree from the Columbia College of Physicians and Surgeons, New York, trained as a clinical associate at the National Cancer Institute (NCI), Bethesda, Maryland, and was a postdoctoral fellow at the University of Birmingham, England, in immunology. He returned to the National Institute of Dental Research and subsequently headed the Section of Cellular Immunology there and, since 1983, has been head of the Laboratory of Molecular Immunoregulation, NCI-Frederick.
The Role of Cytokines in Host Defense and Repair
The largest subfamily of cytokines, known as chemokines, specializes in directing the migration and homing of inflammatory leukocytes, immunocompetent lymphocytes, endothelial cells, and dendritic cells. Chemokines have been shown to contribute to fetal development, hematopoiesis, inflammation, immune responses, angiogenesis, tumor growth and metastatic spread, antimicrobial activities and lymphoid tissue organogenesis. They utilize seven transmembrane G-protein coupled receptors GPCR).
Chemokines also promote the adhesiveness of target cells and regulate angiogenesis and may therefore promote tumor growth. We demonstrated that CXCR4 is the only chemokine receptor that is upregulated on endothelial cells (EC) by angiogenic factors such as VEGF and bFGF. The ligand for CXCR4, SDF-1, was found to be chemotactic for EC and to be angiogenic in a number of in vitro and in vivo assays. We are finding that about 50 percent of human melanomas and breast cell cancers spontaneously produce SDF-1 and will investigate whether they use SDF-1 to induce their own blood supply. Similarly, we have documented that MCP-1 and eotaxin are angiogenic and antiMCP-1 partially inhibits the growth of MCP-1 producing tumors. Most recently we have established that endogenous Grm/Gremlin and Dan by interacting with Slits become potent inhibitors of monocyte chemotaxis. Furthermore, these moieties have anti-angiogenic activities. The anti-tumor activities of these agents will be investigated.
We have observed that IL-8 induction of neutrophil degranulation results in the release of several immunostimulating molecules. This includes the alpha-defensins, which have been found to be chemotactic for a subset of resting naive T lymphocytes and immature dendritic cells (iDC). The epithelial cell-derived beta-defensins have been shown to use the chemokine receptor for CCL20/LARC, CCR6, as their receptor. Consequently, although the defensins are relatively small 3.5-4.0 kD molecules with direct antimicrobial activity, they also function as 'microchemokines' and act as signals from the innate host response that galvanize adaptative immune responses. Another antimicrobial peptide cathelicidin interacts with PFRL-1 and also activates in vivo immune responses. Several additional endogenous proteins with antimicrobial activities, namely eosinophil derived neurotoxin (EDN)and high mobility group box 1 protein (HMGB1), have been shown to have chemotactic as well as activating effects on immature dendritic cells. We have shown that EDN, like HMGB1, is chemotactic for a pertussis toxin sensitive GiPCR on iDC and in addition interacts with toll-like receptor 2 (TLR2) to activate and induce the maturation of these iDC. All these proteins appear to function as endogenous warning signals, which we have termed, that alert the immune system. Since all these endogenous alarmins are potent immunostimulant, they may prove to be useful as vaccine adjuvants in antitumor vaccines.
We have shown that chemokine and opioid receptors cross desensitize one another; and by diminishing anti-pain activity in vivo this results in enhancing inflammation associated pain. This receptor cross-talk involves phosphorylation of the receptors by PKC isotypes. Analogous desensitizing receptor cross-talk has been shown between VIP, adenosine and chemokine receptors. Opioid receptors are coexpressed along with chemokine receptors on neurons of the dorsal root ganglion (DRG). Furthermore, such neurons also express vanilloid pain receptors, which we have shown can be 'sensitized' and primed to respond to capsaicin by prior stimulation of chemokine receptors. Thus, this receptor 'cross-talk' also enhances the pain associated with inflammation. Furthermore, adenosine by interaction with the A2a GPCR cross phosphorylates and inactivates chemokine receptors. Thus accounting for the anti-inflammatory and immunosuppressive effects of adenosine. These observations suggest the interesting hypothesis that receptor cross-talk between GiPCR and even with non-GiPCR may result in a signaling network with many biological consequences.
This page was last updated on 11/8/2013.