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Tsuneyasu Kaisho Halting the inflammation overload Researchers discover a key molecule involved in regulating our immune response Figure PDLIM2 has two major activities, polyubiquitination of p65 for subsequent degradation and intranuclear targeting of p65 into nuclear bodies. The control (left) shows expression of p65 (stained in red) in the nucleus. The central image demonstrates the absence of nuclear p65, suggesting that p65 is degraded when PDLIM2 is present. The image on the right shows that PDLIM2 transports p65 into nuclear bodies. In this image, the red spotty staining represents the nuclear bodies where p65 has accumulated, since this PDLIM2 mutant has impaired ubiquitin ligase activity and intact intranuclear trafficking activity. © Nature Immunology/Nature Publishing Group/8/587 (2007) Our immune system protects us against microbial pathogens that invade our cells and cause illness. When receptors on the cell surface detect microbes, a cascade of signals and activities within the cell is triggered, resulting in inflammation, which is part of our early defense against pathogens.    Immunologists from the RIKEN Research Center for Allergy and Immunology, Yokohama, and the Harvard School of Public Health, US, recently published a study on the regulation of this system. Without regulation, an unstoppable immune reaction leads to excessive inflammation, which causes conditions such as asthma and arthritis.    The researchers studied a molecule called NF-κB that contains two different subunits known as p65 and p50 and normally resides in the cytoplasm of cells. When this molecule receives the appropriate signal, it enters the cell nucleus and switches on immunoregulatory genes that encode pro-inflammatory molecules. If the process is not stopped, the immune reaction continues. To terminate this reaction promptly, it is important that the p65 molecule that starts this sequence of events is degraded once it has done its job.    RIKEN’s Tsuneyasu Kaisho and his team have identified a pathway that leads to the degradation of p65. Their work shows that the process involves the specific attachment of the protein molecule ubiquitin to p65 followed by transportation of the ‘ubiquitinated’ p65 to distinct sub-nuclear domains, called nuclear bodies, where it is ultimately degraded by the proteins found there (Figure).    Critically, the researchers have described a factor called PDLIM2 that has two highly important roles in the regulation of the immune response. It helps ubiquitin to bind to p65 and then targets this complex to the appropriate nuclear bodies for degradation.    The team showed that PDLIM2-deficient mouse cells had uncontrolled immune responses due to the constant activity of NF-κB and augmented production of molecules that cause inflammation. In vivo studies showed mice lacking PDLIM2 were more sensitive to stimulation of the immune response than mice with normal levels of the molecule.   Developing treatments for inflammatory and autoimmune diseases by modifying the PDLIM2-mediated pathways to terminate NF-κB p65 activation is the future aim of the team. According to team member, Takashi Tanaka, the next step towards this goal is to clarify how PDLIM2 activity itself is regulated. This is very important for developing a way to modify its activity in living cells, he says. Takashi Tanaka ORIGINAL RESEARCH PAPER Tanaka, T., Grusby, M.J. & Kaisho, T. PDLIM2-mediated termination of transcription factor NF-κB activation by intranuclear sequestration and degradation of the p65 subunit. Nature Immunology 8, 584–591 (2007). 6 This article is reproduced from RIKEN RESEARCH with permission http://www.rikenresearch.riken.jp/research/280/
How eating cell ‘corpses’ reduces inflammation Specialized immune cells orchestrate proper elimination of dead cells to prevent inflammation Masato Tanaka Figure Normal (top) and inflamed spinal cord (bottom). The multiple sclerosis-like disease occurs when specialized macrophages that prevent inflammation are depleted. © J. Clin. Invest./ American Society for Clinical Investigation /117/2273 (2007) Reporting in the August issue of The Journal of Clinical Investigation, a team of Japanese researchers has found that immune cells called ‘marginal zone macrophages’ prevent inflammation by promoting the elimination of cells that have just died—so-called cell ‘corpses’. It has been long known that certain types of dead cells can suppress inflammation. A cell ‘programmed’ to die goes through a tranquil process called apoptosis, whereas traumatically killed cells die by a process called necrosis. Only apoptotic corpses can suppress inflammation. Led by Masato Tanaka at the RIKEN Research Center for Allergy and Immunology, Yokohama, the team observed that apoptotic corpses injected into experimental mice migrate to specific locations in the spleen and lymph nodes and then disappear—phenomena associated with suppression of experimentally-induced inflammation. Intriguingly, marginal zone macrophages are found in the same locations. Testing whether the macrophages were important for the disappearance of the corpses and reduced inflammation, the team depleted the macrophages from mice and then injected apoptotic cells. They found that the corpses were present much longer and experimentally-induced brain inflammation could no longer be suppressed (Figure). Digging deeper to understand this, the team looked at other nearby immune cells and found differences in two types of cells called dendritic cells, one of which was known to suppress inflammation. Studying how the two types of dendritic cells responded to apoptotic corpses when the macrophages were present or absent, Tanaka’s team found that the dendritic cell type known to suppress inflammation could do so only when the macrophages were present. In the absence of the macrophages, the other dendritic cells caused inflammation. Further observations indicated a difference in the way the dendritic cells responded to the apoptotic corpses––which are normally ‘eaten’ by the inflammation-suppressing dendritic cells. The team noticed that when the macrophages were absent, the second type of dendritic cells could ingest the apoptotic corpses, which caused inflammation. “We are now currently investigating the differences between the two [types of] dendritic cells,” says Tanaka. One possibility is that the specialized macrophages transport apoptotic corpses selectively to the dendritic cells that suppress inflammation, thus physically preventing the other type of dendritic cells from promoting inflammation. Exactly how marginal zone macrophages and two types of dendritic cells effect this complex processing of apoptotic corpses remains unknown, says Tanaka. Nevertheless, the observations are clear and represent a potential interesting avenue of research in causes of inflammation. Yasunobu Miyake (left) and Hitomi Kaise (right) ORIGINAL RESEARCH PAPER Miyake, Y., Asano, K., Kaise, H., Uemura, M., Nakayama, M. & Tanaka, M. Critical role of macrophages in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. The Journal of Clinical Investigation 117, 2268–2278 (2007). This article is reproduced from RIKEN RESEARCH with permission http://www.rikenresearch.riken.jp/research/326/ 7
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