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Published online before print July 19, 2006
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* Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland; and
Laboratory of Molecular Immunoregulation, National Cancer Institute, NIH, Frederick, Maryland
1 Correspondence: Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, Maryland 20892. E-mail: hrosenberg{at}niaid.nih.gov
This manuscript was selected as a Pivotal Advance because it demonstrates an interesting and heretofore unrecognized role for nitric oxide in short-circuiting an important and similarly unrecognized proinflammatory pathway. Specifically, Dr. Yoshiro Kobayashi and his colleagues previously demonstrated that uptake of apoptotic cells induced cultured macrophages to produce proinflammatory cytokines, including IL-8. In this study, they conclude that nitric oxide (NO) can inhibit the synthesis of soluble inflammatory mediators produced in macrophage culture in response to apoptotic cells.
Yoshiro Kobayashi: Actually, I was surprised to learn that this manuscript was selected as a Pivotal Advance. When we first submitted this work to the Journal of Immunology, the reviewers asked for more molecular studies and questioned the relevance of our findings. Nevertheless, the manuscript was rejected even after considerable modifications were made which emphasized the biological relevance of our findings. The reviewers for the Journal of Leukocyte Biology also requested more mechanistic studies, but accepted our revised paper. I am glad that we persisted.
Dr. Kobayashi, in this work, you show us that the specifics and nature of mediator production depends on whether or not macrophages were cultured with early or late apoptotic cells, or necrotic cells. What specifically are the macrophages responding to?
YK: Well, that is an interesting question, but currently I have no idea what molecules the macrophages are responding to. We don’t know why or how apoptotic cells induce signal transduction in macrophages. We did not expect this result at all—if anything, we thought that the macrophages might be producing antiinflammatory cytokines. We did not expect the presence of apoptotic cells to initiate a proinflammatory response. Furthermore, since NO is well-known to be an antimicrobial product of macrophages, we investigated it and found that it was produced by macrophages incubated with early but not late-stage apoptotic cells.
What do you see as the most novel and interesting parts of this work? Can you relate some of these studies to your interests in tumor immunology?
YK: The role of NO in regulating the responses of macrophages to apoptotic cells is quite novel, as is the observation that the uptake of apoptotic cells results in the production of proinflammatory mediators. From a pathophysiologic standpoint, there is significant production of apoptotic cells in response to anti-tumor interventions such as radiation and chemotherapy. We would like to use gene-deleted mouse models to evaluate the role of NO in modulating macrophage responses in vivo, specifically in the setting of anti-tumor responses and pharmacologic interventions. Perhaps tumors also produce NO, and by blocking this pathway, we might augment the anti-tumor inflammatory response.
Dr. Kobayashi, can you tell the readers of the Journal of Leukocyte Biology about your educational and professional background and interests?
YK: My career path has been an interesting one. There were no formal courses on immunology when I was an undergraduate student. However, I did find a textbook discussing tumors and the potential of anti-tumor vaccines, and I became fascinated with the possibilities of immunology and its role in cancer biology. This interest has given focus to the studies currently in progress in my laboratory.
As for my education and professional background, I received my Ph.D. degree from the University of Tokyo, and then did one year of postdoctoral training at Cancer Institute at Tokyo in the laboratory of Dr. Yoji Ikawa. In Dr. Ikawa’s laboratory, I studied the subcellular localization of membrane glycoprotein gp55 encoded by the Friend strain of spleen focus-forming virus [1
], a protein associated with inducing erythroblast mitosis and erythroleukemia [2
, 3
]. Subsequently, I held a position as Research Associate in the laboratory of Professor Toshiaki Osawa, also at the University of Tokyo, where we were successful at developing cytokine-producing human T cell hybridomas [4
5
6
7
]. I then had the opportunity to come to the United States to study phosphorylation and processing of IL-1
at the National Cancer Institute in Frederick, Maryland, in the Laboratories of Dr. Joost Oppenheim and Dr. Kouji Matsushima [8
]. I then returned to Japan to take a position of Associate Professor at Toho University in 1989, where I was promoted to Professor in 1993.
Much of your recent work focuses on the interaction of professional phagocytes with apoptotic cells. How did you first become interested in this field of study? What most intrigues you about this topic?
YK: About ten years ago, I read a paper in Trends in Immunology describing the production of antiinflammatory cytokines by macrophages that had been stimulated to take up apoptotic cells. I decided to embark on a project aimed at identifying the receptor for this uptake. This goal has not yet been reached, but many interesting observations have been made along the way. For instance, Drs. Savill, Haslett, and their colleagues suggested that the macrophage response to phagocytosis of apoptotic cells was not inflammatory, based on the absence of thromboxane B2 in co-culture experiments [9
, 10
]. However, we noted that cytokine production by macrophages had not been examined in these experiments. So I became interested in this field with expectation that macrophages co-cultured with apoptotic cells would produce primarily antiinflammatory cytokines. Much to our surprise, we found the production of proinflammatory MIP-2, but not other cytokines, including TNF-, IL-1, IL-1ß, IL-1R, and IL-10. Since then, the pathological significance and the regulatory mechanisms underlying MIP-2 production have been the most interesting to us and represent crucial directions for our work. The next big step will be to reveal the role of NO in directing MIP-2 production in vivo.
On a more personal note—as someone who has experienced scientific life both in the United States and Japan, can you comment on what you see as the major differences between your experiences in the United States and Japan, scientific and otherwise?
YK: I was somewhat older than most postdoctoral fellows when I arrived at the NCI, so perhaps I have a different perspective, as it was certainly wonderful to be able to focus on work without too many other distractions and responsibilities. I enjoyed lab work both in the United States and Japan, but I was very much impressed with having the chance to learn from and to interact with many excellent researchers at the NCI who came to study there from all over the world. At the NCI, I found many researchers specifically concerned with physiologic relevance and clinical application, which I found particularly inspiring. As a Japanese Christian, I was able to attend church regularly while in the United States and also to make many new friends outside the NCI community. Nowadays, with so many excellent Japanese scientists, many young Japanese researchers can stay in Japan for postdoctoral training, and I am afraid that young people will not take the important opportunity to become exposed to outstanding researchers and research environments in other countries. I would like to encourage them to leave Japan for a short while and see what there is to be learned from others.
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