Published online before print July 3, 2006
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Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland
1Correspondence: Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892. E-mail: hrosenberg{at}niaid.nih.gov
This work was selected as a Pivotal Advance because it features two well-known mediators of angiogenesis—vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)—as having unique and unexpected roles in potentiating leukocyte responses to specific inflammatory stimuli.
We would like to tell the readers of JLB a bit about you personally, and about your life in science. Can you tell us who was a significant influence in your professional life and work?
My father and grandfather, Drs. Bela Issekutz, Jr. and Sr., respectively, were the most influential persons in determining the selection of a career in science. They were born in Hungary, as was I, and pursued physiology and pharmacology careers. My father’s specific interests were endocrinology and energy metabolism during fasting, exercise, and diabetes. My brother, Dr. Thomas Issekutz, and I started our research under his guidance and then moved on to pursue immunology research in the 1970s. I consider myself very fortunate to have had two generations of scientists as role models. I learned from my father the concept of viewing the entire organism and its responses to physiologic perturbations. As a result, much of my interest is in dynamic processes such as inflammation and the interplay between cell types and soluble factors, especially in vivo.
Can you tell us more about why you chose to do this work as well as about the novel roles you have defined for bFGF and VEGF?
First, I would like to recognize my co-author, Dr. Sandra Zittermann, who is a very talented postdoctoral fellow with my group. I would also like to recognize her mentor, Dr. Eduardo Chuluyan of University of Buenos Aires, Argentina, who was also among the finest postdoctoral fellows I have had the pleasure of mentoring, and who referred Sandra to me for further training. Sandra will soon be continuing research training with Dr. Jorge Filmus at the University of Toronto in signaling in carcinoma cells.
With respect to the work presented in the manuscript—– the vast majority of the work on vascular endothelial growth factor (VEGF) and fibroblast growth factor (bFGF) has focused on the role of these mediators in promoting blood vessel growth in a tumor setting or wound healing. However, angiogenesis also occurs at sites of inflammation, typically during chronic inflammation. Several experiments, including those by our group have shown that these mediators clearly interact with and activate endothelial cells, and have indicated that VEGF and bFGF down-regulate leukocyte recruitment mechanisms [1 , 2 ]. Thus, the prediction was that they would inhibit leukocyte recruitment in an inflammatory setting. However, as we show here, this prediction was wrong. We found that bFGF and VEGF act differentially, but synergistically with one another to potentiate leukocyte recruitment in response to inflammatory stimuli. This result was really quite surprising.
Was there anything about this work that was particularly unexpected or controversial? Was there any aspect of this work that was a "hard sell" to the scientific community?
Interestingly, there were some hints in the literature suggesting that FGF and VEGF might potentiate leukocyte recruitment. Specifically, I’m thinking of the work by Ballermann’s group [3 ] which demonstrated that soluble FGF receptor diminished the inflammatory response in allograft vasculopathy. Similarly, Cattini’s group [4 ] demonstrated that increased expression of bFGF augmented the inflammatory response in a mouse model of myocardial injury.
We actually expected there to be more controversy, as several earlier studies suggested that VEGF and bFGF might actually inhibit leukocyte recruitment. We were pleasantly surprised and gratified to find that our work has been readily accepted by our scientific peers. I credit Dr. Zittermann and her thorough and sound work in making the findings convincing.
What are some of the future directions for this work?
We are interested in looking at the survival and rate of clearance of the leukocytes recruited in the presence of bFGF and VEGF, which are studies that need to be performed in vivo. Similarly, we are quite interested in determining the consequences of inhibiting endogenous bFGF and VEGF, particularly as to effects on leukocyte accumulation in immuno-inflammatory conditions such as arthritis and asthma models.
Do you have any specific ideas or plans regarding the role of these mediators in the pathogenesis of arthritis or other inflammatory conditions?
Certainly, anti-angiogenic therapy has been reported to decrease severity of experimental arthritis, but it is too early to comment on the efficacy of such treatments in human arthritis. Our work adds a new dimension to these treatment studies by suggesting that, at least in some cases, anti-angiogenic therapies targeting VEGF and/or FGF may also elicit previously unappreciated effects on leukocyte recruitment. Our work here and in our previous publication [5 ] suggests that bFGF can potentiate leukocyte recruitment without tachyphylaxis, suggesting that there are both acute and sustained effects of this growth factor that are not related to angiogenesis. We hope that other scientists consider joining us in exploring the unanticipated actions of these mediators.
What do you enjoy most about the scientific pursuit?
I enjoy discovering new knowledge, particularly when that knowledge provides insight into human disease and treatment strategies. I enjoy working with trainees and instilling them with enthusiasm for the scientific endeavor. It’s like "reliving one’s youth" when working with good trainees, particularly when sharing the excitement of new discoveries.
What advice would you give to young scientists about to enter the profession?
It is important for young scientists to understand that a career in research will always have its ups and downs. That said, it is also a career that will always be very intellectually challenging and exciting, as well as essential and satisfying. A young scientist should remain flexible at all levels. One must remember to not get discouraged, to seek out good mentors and to stay open to a variety of research directions and funding options. I tell them that scientific curiosity, talent, and hard work can be focused on a variety of important scientific questions, many of which are likely to yield important new knowledge.
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Figure 1. Dr. Sandra Zittermann earned her Ph.D. degree in 1999 at the University of Buenos Aires, Argentina, and is completing a postdoctoral fellowship in Dr. Issekutz’s laboratory. Dr. Andrew Issekutz received his M.D. degree from Dalhousie University in 1974 and did a residency in pediatrics at Dalhousie University. He completed postdoctoral research and clinical training in immunology at the Hospital for Sick Children in Toronto and in experimental pathology at the University of Toronto. He has been at Dalhousie University since 1979, and currently holds the title of Professor of Pediatrics, Pathology and Microbiology-Immunology.
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