| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
1 Correspondence: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892. E-mail: hrosenberg{at}niaid.nih.gov
In this manuscript, you report that CD163 is released from monocytes in response to selective activation of cell surface TLRs 2, 4, and 5. This discovery reveals the broad outreach of TLR activation, which includes hematologic, metabolic, as well as immunologic consequences. Can you tell us more about your interest in this subject?
Paul Guyre: I have a long-term interest in the physiology, function, and responses of monocytes and macrophages, which has been a major research focus since my postdoctoral fellowship with Dr. Allan Munck, who first discovered glucocorticoid receptors. My work initially gravitated toward understanding how glucocorticoids and cytokines regulate Fc receptors for IgG [1 ], and this led to our discovery of the glucocorticoid-induced macrophage-specific glycoprotein now known as CD163 [2 ].
Can you embellish a bit on your scientific background, particularly any trials and tribulations, excitements, and successes during your earlier years?
P. G.: My first "big break" came when I was searching for a GRMF (glucocorticoid response modifying factor) and discovered a molecule that we called a FRAP, for Fc receptor augmenting protein. Interestingly, FRAP turned out to be gamma interferon [3 ]. It was exhilarating when the raw counts came off the gamma counter, showing 125-I IgG binding to monocytes, which were 10-times higher instead of 50% lower, which was what we originally anticipated. Later, thanks to a multi-parameter hybridoma screening method perfected by Barbara Vance and Peter Morganelli, we isolated monoclonal antibodies to a protein we then called p155 (now we know it as CD163), a molecule suppressed by IFN-gamma and up-regulated by glucocorticoids, which was again the opposite of what we had originally planned.
A larger interest soon emerged regarding the roles played by stress hormones and cytokines in leukocyte activation, sepsis, and inflammatory stress. Certainly, an interest in Toll-like receptors follows naturally from this scenario [4 ]. CD163 resurfaced during our collaboration with Dr. Mark Yeager of the Department of Anesthesiology and Critical Care Medicine at Dartmouth-Hitchcock Medical Center, since CD163 has been characterized as a glucocorticoid and cytokine-regulated component of the stress response and has been identified in serum during endotoxemia in vivo [5 , 6 ].
Lehn, as an MD/PhD student, can you tell us a little about your background, what brought you to this project, and where you hope this work will take you in your career?
Lehn Weaver: I’m originally from Pennsburg, Pennsylvania, which is a small town northwest of Philadelphia. I graduated from Susquehanna University with an interest in science, but I was unsure as to whether I wanted to pursue a career as an M.D. or a Ph.D, so I decided to obtain training in both disciplines at Dartmouth. I selected Dr. Guyre’s group because I could see the clear translational aspects to the work taking place in his laboratory. I really appreciated the opportunity to work on this particular project because so little is known about CD163, and thus there is the huge potential to find out new things and make great steps forward. I hope to finish up work in the lab this summer and return to medical school. Although I have not decided on a clinical specialty, my career plans are likely to include academic medicine with a focus on how the immune system affects human health and disease.
You said that you particularly liked the translational aspects of Paul’s work, can you embellish on this a bit?
LW: Among the translational features of this work, Paul’s lab in collaboration with Dr. Michael Fanger of the Department of Microbiology and Immunology at Dartmouth Medical School had previously made monoclonal antibodies against Fc gamma RI that showed promise for treatment of autoimmune diseases [7 ] and there is certainly significant interest in the translational applications of our CD163 research with respect to cardiovascular disease and coronary artery bypass surgery [6 ]. I am particularly interested in potential therapies relating to soluble CD163 as we continue to try to elucidate its biological importance.
A question for each of you in turn—what directions do you see this work taking in the near and, if you can predict, the more distant future?
LW: So far, we have focused on TLR agonists that regulate CD163 expression acutely. We are currently evaluating CD163 expression over longer time periods in order to gain a better understanding of how pattern recognition receptors influence CD163 expression and shedding from human monocytes.
PG: We also have some favorite theories that I would like to pursue. Among these is the possibility that CD163 may have physiologic roles beyond scavenging haptoglobin:hemoglobin complexes. As noted earlier, both glucocorticoids and IL-10 markedly increase CD163 expression and there is a significant increase in serum levels of soluble CD163 during sepsis and endotoxemia. CD163 might serve in a regulatory, antiinflammatory role by protecting against oxidative stress induced by free hemoglobin, but perhaps also through other interactions with LPS. While there is presently little data to support this, the possibilities are there, and are definitely worth further study.
|
|
Related Article
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
