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Vasoactive intestinal peptide, periodontal disease, and the innate immune response: an interview with Dr. John J. Taylor

2007; Oxford University Press; Volume: 81; Issue: 4 Linguagem: Inglês

10.1189/jlb.1306086

1938-3673

Helene F. Rosenberg,

Antimicrobial Peptides and Activities

Vasoactive intestinal peptide (VIP) is a neuroendocrine peptide with far-reaching effects on the immune response. In this Pivotal Advance manuscript, Dr. John J. Taylor and his colleagues demonstrate that VIP can inhibit LPS-induced differentiation of monocytes into macrophages and concomitant TLR up-regulation. JJT: VIP was discovered in intestinal extracts in 1970 by Said and Mutt [1] as the result of a search for a vasodilatory mediator responsible for hypotensive shock. Because VIP was initially detected in neuronal tissue, it was characterized as a component of the neuroendocrine system. We now know that VIP is also produced by mast cells and Th2 lymphocytes. During the past 25 years, several research groups, most notably that of Mario Delgado at University of Seville in Spain [2], have focused attention on the role of VIP in modulating innate and acquired immune responses. Our interest in VIP, its interactions with TLRs, and its role in promoting monocyte/macrophage differentiation emerged from three distinct directions. First, of course, is my collaboration with Dr. Philip Preshaw, a periodontist in the School of Dental Sciences, University of Newcastle upon Tyne, UK. Philip is a dentist by training; however, we are both interested in the role of cytokines in periodontal diseases, particularly the IL-1 family and their responses to and interactions with the bacterial product, LPS. In particular, we have focused much of our attention on the pathogen, Porphyromonas gingivalis, which is a gram-negative bacterial species that promotes periodontal disease. Together, we were intrigued by the work of Rosa Gomariz and colleagues from Universidad Complutense in Madrid, Spain. This group has shown that administration of VIP to mice with trinitrobenzene sulfonic acid (TNBS)-induced colitis (which is a model of Crohn’s disease) results in diminished disease in correlation with diminished expression of TLRs 2 and 4 in macrophages, dendritic cells, and lymphocytes [3]. While earlier studies suggested that VIP could interfere with TLR-mediated signal transduction, this was the first bit of data that suggested that there might be regulatory mechanisms at an earlier stage of the inflammatory response. However, there are some differences in the regulation of TLR expression in mice and humans and most of the research on VIP (including the Gomariz study) has been conducted in murine systems. Our previous work had shown that VIP inhibited cytokine responses to P. gingivalis LPS in human monocytes [4] so we were keen to extend this work to look at TLR expression. Interestingly, the Gomariz group has recently shown that VIP reduces the inflammation-mediated expression of TLR2 and TLR4 in synovial fibroblasts from patients with rheumatoid arthritis (RA) [5]. And finally, Dr. Neil Foster, who was a senior postdoctoral fellow in our laboratory, brought in the direct expertise and interest in VIP immunobiology. While in Paul Barrow’s laboratory at the Institute for Animal Health Compton, UK, Neil worked on animal models of salmonellosis, and showed specifically that VIP could prevent killing and promote growth of S. typhimurim via blockade of IFN-gamma signaling [6, 7]. Neil now has his own lab in the School of Veterinary Medicine and Science at the University of Nottingham, UK. Dr. John J. Taylor in front of St. James’ Park, home of the Newcastle United Football Club. Dr. Taylor received his B.Sc. degreee with honors in Applied Biochemistry from Brunel University, London, and his Ph.D. from the University of Newcastle. After postgraduate work on T cell receptor gene rearrangements and their role in acute lymphoblastic leukemia, he joined the faculty as a Lecturer in Molecular Biology at the School of Dental Sciences, University of Newcastle upon Tyne, UK. JJT: Although our results, standing alone, are certainly novel, we are building on substantial previously published information, mostly from Richard Darveau’s group in Seattle, which defined the interactions between P. gingivalis LPS and TLRs [8, 9]. Specifically, Darveau’s group was the first to characterize the structure and profound heterogeneity of LPS from P. gingivalis, and also to demonstrate that P. gingivalis bacteria were capable of modifying the LPS structure even further in response to signals from the environment [9, 10]. This is in contrast to E. coli, which has structurally uniform and constant LPS. JJT: Certainly with regard to oral bacteria, the information on the lipid A components is somewhat limited and the best studied species is P. gingvalis. Certainly some oral bacteria have similar structures to E. coli, but others, such as P. gingivalis, are variable and unique [8]. To the best of my knowledge, no one has yet explored the responses of P. gingivalis to changes in real environments in vivo, although one might expect such changes to LPS structures to occur. JJT: Nathalie Carayol and colleagues [11] explored the responses of differentiated THP-1 cells to P. gingivalis LPS via an extensive gene microarray analysis. While the focus of their work was the identification of NF-kB dependent pathways, it was clear to us that not all of the differential regulation observed could be explained within the confines of this mechanism. This suggested to us that other transcription factors were probably involved. Indeed, as we noted in our manuscript, in human cells, expression of TLR2 and TLR4 is not regulated by NF-kB [12]. Although we have not examined PU.1 in peripheral blood monocytes, VIP certainly inhibits LPS-induced TLR expression in these cells as shown in our paper. JJT: Periodontal disease is interesting for many reasons, one of which being that it is just so commonplace. It is so prevalent that most people probably don’t even perceive it as a disease, but tooth loss from periodontal disease can have profound health consequences, and economically it is an important disease in healthcare terms. Interestingly, periodontal disease has quite a bit in common with rheumatoid arthritis (RA). Both diseases involve tissue destruction mediated by the IL-1 family of proinflammatory cytokines, and both involve the actions of matrix metalloproteinases (MMPs), with resulting destruction of, in the case of RA, inter-articular joints, or, in the case of periodontal disease, ligaments and bone that hold the teeth in their proper place and position. As to therapy—my colleague Philip Preshaw is involved in a clinical trial that is evaluating MMP-modifying strategies in periodontal disease, similar to those proposed for use in RA [13]. Similarly, other cytokine inhibitors (IL-1 / TNF-α antagonists) used in RA could be considered for periodontal disease [14]. In general, periodontal research is a bit behind many other fields in terms of rational therapeutics, but if we can base some of our strategies on what has already been determined for RA, we may catch up quickly. JJT: I actually come from Newcastle originally, which is in northeastern part of England. Many people in Newcastle (including myself) are mad about football, which of course is called soccer in the US. Until I sustained a knee injury earlier this year, I played football in an adult league. Now I am focusing on learning golf with my 11 year old son. JJT: I just wanted to mention how happy I was to have this paper accepted for publication in Journal of Leukocyte Biology. I think there are many important basic and clinical biologic implications of periodontal disease, and perhaps articles such as this will lead to more interest from researchers studying inflammatory processes.