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While it has long been suspected that inflammation participates in the pathogenesis of metabolic disorders such as the insulin resistance that occurs in type 2 diabetes, recent work suggests that this is not the only important interaction between metabolism and inflammation. Inroads into the understanding of the relationship between metabolic pathways and inflammation are indicating that signaling by innate immune receptors such as TLR4 and Nlrp3 regulate metabolism. TLRs have been shown to promote glycolysis, whilst Nlrp3‐mediated production of IL‐1β causes insulin resistance. A key role for the hypoxia‐sensing transcription factor HIF1α in the functioning of macrophages activated by TLRs has also recently emerged. This review will assess recent evidence for these complex interactions and speculate on their importance for innate immunity and inflammation.
Conference Article| June 01 1988 Effect of interleukin-1 on free arachidonic acid levels in human synovial cells L. A. J. O'NEILL; L. A. J. O'NEILL 1Department of Pharmacology, Royal College of Surgeons, Lincolns Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar G. P. LEWIS G. P. LEWIS 1Department of Pharmacology, Royal College of Surgeons, Lincolns Inn Fields, London WC2A 3PN, U.K. Search for other works by this author on: This Site PubMed Google Scholar Biochem Soc Trans (1988) 16 (3): 286. https://doi.org/10.1042/bst0160286 Article history Received: November 24 1987 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Citation L. A. J. O'NEILL, G. P. LEWIS; Effect of interleukin-1 on free arachidonic acid levels in human synovial cells. Biochem Soc Trans 1 June 1988; 16 (3): 286. doi: https://doi.org/10.1042/bst0160286 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Society Transactions Search Advanced Search Keywords: IL-1, interleukin 1, PGE2, prostaglandin E2, AA, arachidonic acid, PC, phosphatidylcholine, PI, phosphatidylinositol, PS, phosphatidylserine, PE, phosphatidylethanolamine This content is only available as a PDF. © 1988 Biochemical Society1988 Article PDF first page preview Close Modal You do not currently have access to this content.
The Toll/interleukin-1 receptor (TIR) domain is conserved in the intracellular regions of Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) as well as in several cytoplasmic adapter molecules. This domain has crucial roles in signal transduction by these receptors for host immune response. Here we report the crystal structure at 2.3-Å resolution of the TIR domain of human IL-1RAPL, the first structure of a TIR domain of the IL-1R superfamily. There are large structural differences between this TIR domain and that of TLR1 and TLR2. Helix αD in IL-1RAPL is almost perpendicular to its equivalent in TLR1 or TLR2. The BB loop contains a hydrogen bond unique to IL-1RAPL between Thr residues at the 8th and 10th positions. The structural and sequence diversity among these domains may be important for specificity in the signal transduction by these receptors. A dimer of the TIR domain of IL-1RAPL is observed in the crystal, although this domain is monomeric in solution. Residues in the dimer interface are mostly unique to IL-1RAPL, which is consistent with the distinct functional roles of this receptor. Our functional studies show IL-1RAPL can activate JNK but not the ERK or the p38 MAP kinases, whereas its close homolog, TIGIRR, cannot activate JNK. Deletion mutagenesis studies show that the activation of JNK by IL-1RAPL does not depend on the integrity of its TIR domain, suggesting a distinct mechanism of signaling through this receptor.
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A central unifying principle in the field of signal transduction has been the covalent modification of proteins by phosphorylation. A wide range of protein kinases are known, and the process is regulated by a more limited although important number of protein phosphatases. Recently, there has been a remarkable increase in the numbers of examples of another reversible covalent modification in proteins during signaling, ubiquitination. Historically, the function of ubiquitination was to cause protein degradation in the 26 S proteasome. The difference lies in the type of ubiquitin chain: if the linkage to the target protein is via Lys48 on ubiquitin, this will lead to a series of events that culminate in degradation of the polyubiquitinated protein by the 26 S proteasome. Also, there have to be a minimum of four ubiquitins attached in order to trigger degradation. However, if the polyubiquitin chains are linked via Lys63, this will direct protein-protein interactions via a ubiquitin-binding domain on the interacting target protein. A major function of this type of ubiquitination appears to be to allow proteins with this domain to assemble into multiprotein complexes, which might lead to access to substrates if kinases are also involved, but also regulates processes such as endocytosis and ribosomal protein synthesis (1Pickart C.M. Fushman D. Curr. Opin. Chem. Biol. 2004; 8: 610-616Crossref PubMed Scopus (853) Google Scholar). The process of ubiquitination is mediated by ubiquitin ligases and is reversed by deubiquitinating enzymes. The best examples of this phenomenon are to be found in the regulation of innate immune signaling, where both phosphorylation and Lys63-linked ubiquitination are the critical covalent modifications that launch signaling pathways activated by innate immune receptors such as the TLRs 2The abbreviations used are: TLR, Toll-like receptor; TNF, tumor necrosis factor; SUMO, small ubiquitin-like modifier. (2O'Neill L.A.J. Immunity. 2008; 29: 12-20Abstract Full Text Full Text PDF PubMed Scopus (301) Google Scholar). Here, we present three minireviews on this emerging and exciting topic that provide important examples of ubiquitination/deubiquitination in signaling. In the first minireview, Sinéad E. Keating and Andrew G. Bowie provide an overview of non-degradative ubiquitination in signaling by innate receptors, particularly the TLRs, but also in response to the pro-inflammatory cytokine interleukin-1 (which, similar to TLRs, signals via the Toll/interleukin-1 receptor domain) (3Keating S.E. Bowie A.G. J. Biol. Chem. 2009; 284: 8211-8215Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). They describe how polyubiquitination is a key activation signal for the transcription factor NF-κB. Various ubiquitin ligases participate, notably TRAF6 (TNF receptor-associated factor) and TRAF3, which were formerly thought to be adapters that linked to kinases and are now known to be E3 ligases. Other ligases include Ubc13, which is an E2 ubiquitin-conjugating enzyme, and the Pellino proteins. Keating and Bowie also remind us that bacteria have deubiquitinating proteases that target TRAF6 and TRAF3. The best example of this is the virulence factor YopJ, which is in Yersinia pestis. The capacity to target ubiquitinated proteins would be expected to limit host-defense signaling pathways. In the second minireview, Beatrice Coornaert, Isabelle Carpentier, and Rudi Beyaert describe the fascinating deubiquitinating enzyme A20 (4Coornaert B. Carpentier I. Beyaert R. J. Biol. Chem. 2009; 284: 8217-8221Abstract Full Text Full Text PDF PubMed Scopus (261) Google Scholar). Although first described as an inhibitor of TNF-induced apoptosis, we now know that a major function of A20 is to limit TLR signaling and to prevent sepsis. A20 is a dual ubiquitin-editing enzyme again in NF-κB signaling. It has a number of targets, notably TRAF2, TRAF3, TRAF6, and RIP1, all of which are deubiquitinated by A20. Most interestingly, it has been found that A20-deficient mice develop profound colitis (5Turer E.E. Tavares R.M. Mortier E. Hitotsumatsu O. Advincula R. Lee B. Shifrin N. Malynn B.A. Ma A. J. Exp. Med. 2008; 205: 451-464Crossref PubMed Scopus (229) Google Scholar). If they are crossed with MyD88-deficient mice, however, there is no disease. The authors describe how commensal bacteria activate TLRs, but instead of driving inflammation via MyD88 and the TRAF proteins, they are kept in check by A20. This indicates the importance of deubiquitinating systems to keep pathways under control. This theme is taken up by Edward T. H. Yeh in the third minireview (6Yeh E.T.H. J. Biol. Chem. 2009; 284: 8223-8227Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar). This minireview describes the SUMO modification and in particular focuses on de-SUMOylation. SUMO is a ubiquitin-like protein that targets many different proteins in multiple processes, including innate immunity, but also the cell cycle, transcriptional control, and viral replication. SUMOylation involves only one conjugating enzyme, Ubc9, and a limited number of ligases. There are a number of de-SUMOylating proteases termed SENP (sentrin/SUMO-specific protease), which are still being characterized. Some respond to inflammatory stimuli such as TNF and are key controllers of SUMOylated proteins. Much progress has been made in defining the biochemical basis for non-degradative ubiquitination and its role in cellular function. The authors and editors hope that this set of reviews will enable researchers in such areas as innate immunity to appreciate the importance of non-degradative ubiquitination for the control of complex signaling processes and possibly inspire further work on this most important event for protein function.
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In the 20th century, immunologists focused much of their attention in deciphering the mechanisms of adaptive immunity. As a consequence, tremendous progress was made in the field of adaptive immunity, including tolerance, mechanisms of MHC restriction, the structure and function of MHC receptors, and development and activation of B- and T-cells. The reason why adaptive immunity was the major focus of immunologists is because adaptive immunity gives vertebrates immunity a memory and is most probably an important aspect of human evolution—responsible not only for enabling cognitive abilities but also general cultural accomplishments. In contrast, innate immunity was sidelined. It was viewed as the most archaic of the two branches of immunity, simple and unsophisticated. Since the discovery of phagocytes by Ilya Mechnikov in 1882 and the investigations of Richard Pfeiffer, a fellow worker of Robert Koch, on “endotoxin,” the concept of innate immunity for almost 100 years was that of a static and nonspecific apparatus. It was seen as an undifferentiated system, engulfing and digesting invaders in contrast to the sophisticated framework of T- and B-cells that have elaborate clonal mechanisms to form a plethora of highly specific antibodies by DNA rearrangement. Almost twenty years ago, Charles Janeway changed our view of the innate immune system, by publishing “Approaching the asymptote” as part of the Cold Spring Harbor Symposium on immune recognition. In this publication, he predicted that there would be molecules that were encoded in the germ line which would recognize the presence of molecules produced by broad classes of pathogens. He called these molecules pattern recognition receptors (PRRs) and the ligands that they recognise, pathogen-associated molecular patterns (PAMPs). Janeway's view was justified in the late 1990s with the discovery of Toll-like receptors (TLRs) and the verification that the innate immune system is actually highly specific, relying on germline-encoded pattern-recognition receptors (PRRs) that have evolved to detect components of foreign pathogens referred to as PAMPs. Over the years, research studies have shown that this system is highly specific in recognising microbial signatures; it has virtues that are equally specific and elaborate as the features of adaptive immunity; for example, TLR4 was found to recognise bacterial lipopolysaccharide (LPS) or endotoxin; TLR2 was found to recognise lipoteichoic acid (LTA) and peptidoglycan; TLR3 was able to sense double-stranded viral RNA; TLR5 was found to recognise bacterial flagellin; TLR7 and TLR8 to sense single stranded viral RNA, whereas TLR9 was found to delicately distinguish between methylated DNA from host DNA and unmethylated DNA from microorganisms. Subsequently, TLRs have been identified as operational centers for both innate and adaptive immunity. Cancer, infection, autoimmune, and allergic disorders involve various complex signaling pathways; however, data accumulates that TLRs are involved in all of these seemingly different entities. Their ability to initiate and propagate inflammation makes them attractive therapeutic targets. By understanding TLR-induced mechanisms, we can design more targeted therapeutic interventions for inflammatory disorders in the future. The ancient system of host defense of our cells is an outstanding target for intervention in the relentless efforts in finding cures. Pharmacological intervention in TLR pathways may potentially hold great therapeutic promise. Although for the past decades corticosteroids and in some instances antibodies were the mainstay of anti-inflammatory treatment, we are now at the stage of evaluating TLR pathway modifying molecules in human diseases; this targeted approach will bring more specificity to the treatment of a wide panel of disorders. Given the body of excellent literature on TLRs in disease, we can be very optimistic that targeting them will prove useful in human disease. In this special issue, we compiled 24 interesting papers on various aspects of human disease ranging from autoimmune disorders via dermatologic disease to cardiovascular and respiratory problems, demonstrating the impact of TLRs in a vast number of disorders and the as-yet unrealized therapeutic potential that is awaiting to be translated from the bench to the clinic.
