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Keywords:

  • Cytokines;
  • Immunotherapy;
  • Innate immunity;
  • TLR

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
  7. Supporting Information

Although there has been a great amount of progress in the 25 years since the first reporting of the cDNA for IL-1α and IL-1β, the history of IL-1 goes back to the early 1940s. In fact, the entire field of inflammatory cytokines, TLR and the innate immune response can be found in the story of IL-1. This Viewpoint follows the steps from the identification of the fever-inducing activities of “soluble factors” produced by endotoxin-stimulated leukocytes through to the discovery of cryopyrin and the caspase-1 inflammasome and on to the clinical benefits of anti-IL-1β-based therapeutics. It also discusses some of the current controversies regarding the activation of the inflammasome. The future of novel anti-inflammatory agents to combat chronic inflammation is based, in part, on the diseases that are uniquely responsive to anti-IL-1β, which is surely a reason to celebrate the 25th anniversary of the cloning of IL-1α and IL-1β.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
  7. Supporting Information

The history of the discoveries of IL-1, shown in the timeline in Fig. 1, begins with investigations into the nature of the endogenous protein produced by leukocytes that causes fever. For centuries, fever has been associated with leukocytic infiltrates. The first papers on the soluble factors from “pus” being pyrogenic were published in 1943 from the Russian émigré Eli Menkin, who injected rabbits with supernatants from leukocytes removed from sterile peritonitis (reviewed in 1). In 1948, the late Paul Beeson reported that an endotoxin-free protein material, also released from rabbit leukocytes, caused a rapid onset fever upon an intravenous bolus injection into rabbits 2.

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Figure 1. Time-line of IL-1 basic discoveries. The key discoveries in the field of IL-1 biology (A) before and (B) after the cloning of IL1 are highlighted, together with the key references.

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For the next 40 years, the intravenous bolus injection of supernatants from leukocytes into rabbits with indwelling rectal thermometers was the most rapid and most reliable bioassay for what would later come to be called IL-1. Many scientists subjected the supernatants to increasing levels of purification but this turned out to be a daunting task. In the 1950s and 1960s, protein purification was in its infancy and the pyrogenic activity of the supernatants was often lost during the most simple of separation methods. Furthermore, there was no silver staining to monitor the level of low amounts of proteins.

I, together with my colleagues, was among those who used human PBMC as the starting source to identify the human pyrogen. The losses during the purification were in excess of 98% and ubiquitous endotoxin with properties/activities very similar to IL-1 was a considerable complication. Nonetheless, in 1977, we reported the purification of human leukocytic pyrogen (LP) and estimated that 5–10 ng/kg produced a fever 3. After the cloning of the IL-1β cDNA 4, the recombinant molecule was shown to produce fever in humans at 1–10 ng per kg body weight 5, 6. No other cytokine is as potent as IL-1 in producing a fever in humans providing evidence that IL-1β is the real “endogenous pyrogen.”

Purifying the pyrogenic property of leukocyte supernatants

Early investigators

In 1955, Elisha Atkins demonstrated a circulating protein during endotoxin fever and termed the activity “endogenous pyrogen” 7. During his dedicated career, Atkins demonstrated that fever from immune and infectious causes was due to endogenous pyrogen. LP and endogenous pyrogen are former interchangeable terms for the pyrogenic property of IL-1.

Patrick Murphy and the late Barry Wood were the first to describe that the rabbit pyrogen had a molecular weight of 14 000–15 000 Da and a neutral isoelectric point (pI) of 7 8. Moving from neutrophils in rabbits to human studies, Bodel and Atkins reported that human PBMC released the pyrogen following de novo synthesis and therefore it was not pre-formed, as was the case with rabbit peritoneal exudate cells 9. The pyrogen was also shown to be produced from human monocytic leukemia cells and Hodgkin's and lymphoma cells 10.

Purification of human LP

In our laboratory, the starting material, human PBMC, was not easily available and the cells required stimulation in vitro to release the pyrogenic activity. To avoid endotoxins, we stimulated PBMC with heat-killed Staphylococcus epidermidis. Sterile columns of 1.8 m packed with 3 L of Sephdex were constructed and evaporation in dialysis bags was used to concentrate, since concentrating devices were not endotoxin free. We isolated a 17 000 Da pyrogenic protein against which we made antibody preparations for use in immunoaffinity columns. Following immunoaffinity purification, active fractions were still pyrogenic but no band was visible on SDS PAGE. To overcome this, the active fractions were radiolabeled with 125I Bolton-Hunter reagent and followed for both radioactivity as well as pyrogenicity, ending up with a single radioactive band of pyrogenic activity with a pI 7 (pI 7 LP) 3. The losses were considerable – starting material of a typical run was three liters (approximately 3000 rabbit pyrogen doses) and recovery only approximately ten pyrogen doses.

Lymphocyte activating factor is human LP

“Soluble factors” that enhanced lymphocyte responses to mitogens and antigens moved immunology from “cellular immunology” to the concept that soluble products from macrophages, as well as lymphocytes, produced “factors” that co-activated lymphocytes 11. The macrophage product was called “lymphocyte activating factor” (LAF) and the T-cell product “T-cell growth factor” (TCGF) and their activities were similar in many assays. The pioneering studies on LAF were performed by Igal Gery, Byron Waksman and Fritz Bach; TCGF was first described by Robert Gallo 12. By 1979, LAF was called IL-1 and TCGF IL-2 13.

Following the purification of the pI 7 LP in 1977 3, we were increasingly aware that LAF had physical properties similar to those of LP. Using a macrophage-dependent T-cell assay developed by Lanny Rosenwasser in the late Sheldon Wolff's laboratory, we tested whether purified LP was active on mouse lymphocytes. In many ways, it was a heretical notion that a human molecule that could cause fever and an elevation of prostaglandins in rabbit brains would also be functional on mouse lymphocytes, given the highly specific nature of the immune response. Nevertheless, the purified LP was indeed highly active and, after 2 years of repeated testing, we wrote that LAF and LP were the same molecule 14.

Multiple biological activities and a new name

The concept that components in leukocyte supernatants possessed multiple properties was initially derived from the work of Kampschmidt and co-workers. These pioneers showed that the hepatic acute-phase-protein-inducing properties of “leukocytic endogenous mediator” also possessed pyrogenic activity 15. In 1980, we reported that the purified pI 7 human LP induced production of serum amyloid A, a protein, which, like C-reactive protein, is a classic marker of the acute-phase response. Thus, by the late 1970s, IL-1 was well on its way to being a thoroughly defined molecule in terms of both chemical characterization and identification of non-pyrogenic biologic properties. From today's standpoint, the multiple biological activities of IL-1 can be considered the birth of “cytokine biology” with the pyrogenic property being the first activity described.

At the time, it was highly contentious that a single molecule caused fever, induced hepatic acute-phase proteins, activated lymphocytes and upregulated prostanoid synthesis without any species specificity. IL-1 was proposed as the “master molecule” inducing the entire spectrum of physiologic, hematologic, metabolic and immunologic upheaval of the host response to infection, trauma and immunologic activation 16. Criticism focused on the lack of an amino acid sequence or rIL-1 to prove that a single molecule could, in fact, possess such a wide and varied spectrum of biological activities. Detractors claimed that the multiple activities were due to a mixture of proteins with similar molecular weights or contaminating microbial products and one paper was published to disprove that LAF and LP were the same molecule 17.

Searching for the cDNA: cloning IL-1

In 1982, cDNA cloning was still in its infancy (the cDNA of only three human genes had been reported), vanadium was used to protect RNA degradation, there were no “kits” and we had no amino acid sequences to construct primers to isolate a cDNA. It was even doubtful that making a full-length cDNA was possible due to RNAses in the PBMC, the source of mRNA for the project; however, we had one advantage, i.e. the antibodies we had made in rabbits to the pI 7 human LP. Together with Phil Auron and Alex Rich, by immunoprecipiating rabbit reticulocytes, we identified the primary transcript as a 36 000 Da protein. This was consistent with the existence of a previously identified large molecular weight LP 18. Andrew Webb then joined this ambitious, high-risk cloning project and, after nearly 2 years, we succeeded in isolating a cDNA that when translated in frog oocytes expressed LAF activity 4. The cDNA in fact translated the IL-1β precursor, which we now know is biologically inactive; however, the frog oocyte most likely contains proteases, which can cleave the IL-1β precursor at the serine protease site close to the caspase-1 site which, upon reflection, was most fortunate.

Early studies had assumed that the pyrogenic activity of leukocyte supernatants was due to a single molecule but, in 1974, we reported two distinct pyrogenic proteins, both having molecular weights in the 15–20 000 Da range. One activity was at the expected isoelectric focusing point (pI 7) but the second activity was at pI 5 18. Today, the issue has been resolved and the pI5 form is identified as IL-1α. A large molecular weight pyrogen, estimated by gel-filtration to be 38 000 Da, was also described 18, which is now known to be the active precursor form of IL-1α.

The cDNA for mouse IL-1α 19 reported by Peter Lomedico and Stephen Mizel was isolated from a cell line, whereas the cDNA for human IL-1β was isolated from PBMC 4; both were first reported just over 25 years ago in November and December 1984, respectively. Soon thereafter, experiments with the recombinant proteins demonstrated that IL-1 was indeed pyrogenic and mediated many facets of the acute-phase response. Thus, the existence of a single, endogenously produced molecule – in this case IL-1 – was proven to cause fever. Subsequently, nearly all the various biological properties of the purified LP have been confirmed with rIL-1. Many more activities have also been discovered and the field of IL-1 biology rapidly broadened to include diabetes 20, hemodynamic shock 21 and bone marrow stimulation 22.

The convergence of IL-1 and TLR activities: the Toll-IL-1R (TIR) domain

Mihai Netea once stated, “Without knowledge of the TIR (Toll-IL-1R) domain of IL-1 receptors, Toll proteins would have remained of interest primarily for Drosophila embryology.” With the reporting of the IL-1R cDNA by John Sims et al. in 1988 23, an entire new field of investigation was possible. Early studies revealed that the cytoplasmic domain of IL-1R has no intrinsic tyrosine kinase activity; rather, the cytosolic domain has 45% amino acid homology with the cytosolic domain of the very distant Drosophila Toll gene needed for the developing embryo 24. All members of the IL-1R and TLR families share this TIR domain. At the time of Gay and Keith's report 24, the ligands for mammalian TLR were unknown (see Fig. 1).

It was also clear from decades of research that IL-1 and endotoxins trigger the same biological responses. For example, the COX-2, iNOS, ICAM-1 and fever response to IL-1 and LPS are nearly the same regardless of the species 25. Since deletion of the TIR domain from IL-1R prevents signaling 26 and the same domain is present in TLR, it should have been obvious that the LPS-unresponsive C3H/HeJ mouse had a defect in the same gene that contained the TIR domain, which turned out to be TLR4 27–29. Thus, the TIR domain is essential for IL-1 as well as LPS (endotoxin) signaling and TLR4 is the receptor for LPS. However, much of this escaped scientists until three independent groups reported that microbial products such as endotoxins were the ligands for TLR 27–29. Today, we have a clear understanding of the duplication of function represented by the TIR domain 30, 31.

Prior to the study by Jules Hoffmann's group in 1996 linking Toll proteins to the immune response 32, there was no dearth of reports on the ability of LPS or IL-1β to provide the host with resistance to infection. Van der Meer et al. had shown that a low dose of rIL-1β protected neutropenic mice against a lethal infection of Pseudomonas33. Thus, the TIR domain common to TLR and IL-1R provided the basis that both families were initiators of inflammation, as well as being required for survival. Today, one can appreciate both roles for IL-1β in humans in that blocking IL-1β reduces inflammation but at the same time increases infections 34.

IL-1 family (IL-1F) and cytokine evolution

The origin of the IL-1F is probably IL-1α because of its close homology to acidic FGF. IL-1α and FGF have receptors that are comprised of Ig-like domains; both IL-1α and FGF are not secreted, are found in the nucleus, are active as unprocessed precursors and become available when the cell dies from necrosis and releases its intracellular contents. Unlike IL-1β, IL-1α is present intracellularly in healthy tissues and translocates to the nucleus where it participates in transcription 35. Intracellular IL-1α is a chromatin-associated cytokine and is highly dynamic in the nucleus of living cells. During apoptosis, intracellular IL-1α concentrates in dense nuclear foci and is not released along with cytoplasmic contents but remains inactive. In contrast, during hypoxic death, the IL-1α precursor is released from cells undergoing necrosis and is biologically active 36, 37. Another member of the IL-1F is IL-33 (IL-1F11). Like IL-1α, IL-33 is constitutive in many cells, is active as a precursor and locates to the nucleus where it functions as a transcription factor 38, 39.

In so many ways, IL-1α is also the story of cytokine evolution. First, cytokines are intracellular growth and repair molecules interacting with DNA as transcription factors but are not secreted proteins. FGF is a classic example. In the starfish, which has an IL-1-like molecule 40, any secreted growth factor needed for regeneration of a severed arm would have been diluted in the seawater and rendered ineffective. Later, when immunoglobulins evolved, they were used for the cell surface receptors and cytokine growth factors found a second life by binding to cell surface receptors.

The era of the inflammasome

IL-1β and the processing of the IL-1β precursor

IL-1β evolved after IL-1α. The distinctive characteristic of IL-1β is the complex pathway by which the inactive precursor is cleaved by caspase-1 within the cell into an active cytokine and secreted. Activation of caspase-1 takes place via a protein complex called the inflammasome 41. The existence of the inflammasome was only possible with the discovery of cryopyrin by Hal Hoffman, which has already been described from an historical perspective 42. The discovery of cryopyrin provided the basis for the understanding of a broad class of acute and chronic inflammatory diseases, uniquely mediated by IL-1β and now known as “auto-inflammatory diseases.” In contrast, extracellularly, the IL-1β precursor can be cleaved by neutrophilic enzymes such as proteinase-3 and other serine proteases into an active cytokine 43. Indeed, in mice deficient in caspase-1, active IL-1β is still produced 43, due to proteinase-3 cleavage of the IL-1β precursor close to the caspase-1 site 44. Furthermore, non-caspase-1 processing of the inactive IL-1β precursor to the active cytokine has also been reported in caspase-1-deficient mice challenged with validated models of inflammation 45.

Activation of the inflammasome

Nearly all studies published to date on the activation of the NLRP3 inflammasome employ microbial products; for example, the induction of IL-1β from urate crystals is achieved in the presence of LPS. However, most inflammation is sterile and IL-1 itself induces the secretion of IL-1β 46. It is likely that IL-1-induced IL-1 drives inflammation in auto-inflammatory diseases 47. In freshly obtained human PBMC 48 and in highly metastatic human melanoma cells 49, the inflammasome is constitutively active. IL-1 stimulates its own transcription and translation, which is the rate-limiting step in cells with constitutively active caspase-1.

IL-1β also induces ROS, and some reports claim that ROS directly activate the inflammasome, causing release of IL-1β 50, as discussed in elsewhere in this Viewpoint series 51. In contrast, there are also reports that the failure to generate ROS does not impair the release of IL-1β. For example, in cells deficient in super oxide dismutase-1, ROS levels are high but caspase-1 is suppressed and IL-1β levels are low 52. The silencing of endogenous super oxide dismutase-1 in human PBMC, resulting in higher ROS, was followed by a 60% lower level of secreted IL-1β 53. In addition, in cells deficient in gp91phox and therefore lacking the ability to generate ROS, silica, urate crystals and ATP each induced IL-1β release 54. In fact, cells deficient in gp91phox produced more, not less, IL-1β 54. Thus, it remains unlikely that ROS are driving activation of the inflammasome and the release of active IL-1β.

Comparable to murine cells deficient in gp91phox, humans with chronic granulomatous disease have a mutation in p47-phox, consequent defective NADPH activity and are unable to generate ROS. PBMC from these patients release processed IL-1β following stimulation with urate crystals. Moreover, levels of IL-1β are fourfold higher compared with PBMC from unaffected controls 55. Although the well-known inhibitor of ROS, diphenylene iodonium, reduces the secretion of IL-1β in all studies, diphenylene iodonium inhibits IL-1β gene expression rather than caspase-1 activity 55. Thus, ROS dampens the inflammasome and this may explain why chronic granulomatous disease patients, who are unable to generate ROS, have increased inflammation with granulomatous lesions and a form of colitis indistinguishable from that found in Crohn's disease. In the broader sense, prevention of ROS suppression of caspase-1 may explain why placebo-controlled trials of anti-oxidants often fail to show benefit or even increase disease severity or deaths 56–58.

Future directions for the IL-1F

IL-1-related diseases and treatment

As shown in Fig. 2, one present direction of the IL-1 story comes from the expanding list of diseases for which reducing the activity of IL-1β is therapeutically indicated. Several diseases responsive to IL-1β blockade are listed in the Viewpoint by Cook et al.59. Treating gout with an antibody to IL-1β may seem “excessive” as the disease in most patients is well-controlled using inexpensive oral drugs; however, for patients with poorly controlled disease, there is a long-term benefit from a short course of IL-1β blockade, which is due to the “auto-inflammatory” nature of these diseases in which IL-1 induces itself. Urate crystals are always present in gouty joints without pain. The trigger for the “attacks” is likely related to the ingestion of certain foods and the benefit of blocking IL-1β may be linked to an arrest in IL-1-induced IL-1.

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Figure 2. Time-line of IL-1 clinical applications. The injection of recombinant IL-1b (as well as IL-1a) in the early 1990s was performed following chemotherapy or bone marrow transplantation in patients with various tumors in order to utilize the hematopoietic properties of IL-1. All subsequent studies on the clinical applications of IL-1 are based on either receptor blockade or neutralization of IL-1b activities in acute or chronic inflammatory diseases (reviewed in 42).

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The most dangerous form of a myocardial infarction occurs in patients with an elevated ST segment in the electrocardiogram. If patients survive the infarction, most subsequently develop debilitating heart failure. In a recently completed study 60, such patients received anakinra for 14 days following the infarction; 14 wk later, the severity of heart failure was significantly reduced. The study raises the question whether chronic heart failure is an IL-1β-driven auto-inflammatory disease. Is type 2 diabetes also an IL-1β-driven auto-inflammatory disease? Blocking IL-1 with either anakinra 61 or antibodies to IL-1β 62 results in improved glycemic control and possibly regeneration of the insulin-producing pancreatic beta cells. In a follow-up study after a 13-wk course of anakinra, there was a 50% reduction in insulin use during the remaining 39 wk 63. The concept that chronic heart failure and type 2 diabetes are driven by the auto-inflammatory circuit of IL-1-induced IL-1 has considerable support from animal studies and clinical research 64–66.

In mice deficient in IL-1β, chemical carcinogenesis was significantly reduced whereas in mice deficient in IL-1Ra, cancer transformation is increased compared with the wild-type mice 67. Chronic inflammation contributes to carcinogenesis and IL-1β may play a significant role. Multiple myeloma is another example for IL-1β in cancer. In multiple myeloma, IL-6 is the primary growth factor for the malignant cells. Patients with smoldering or indolent myeloma are at high risk for advancing to overt disease within 6 months to a year. By reducing endogenous IL-6 production with anakinra, there was a significant reduction in progression to overt multiple myeloma from 6 months to over 4 years in several patients 68. These impressive findings have broad clinical implications because reducing IL-1β activity with anakinra or anti-IL-1β is without the toxicity of chemotherapy regimens. Since IL-1β is a driving force in angiogenesis and reduces VEGF production 69, blocking IL-1β offers an additional benefit in patients with smoldering or indolent myeloma.

A role for IL-1 in the generation of Th17 polarization

Increasing clinical studies indicate that T-cell differentiation into IL-17-producing cells plays a major role in several autoimmune diseases. IL-1 is essential since T cells from mice deficient in IL-1R fail to induce IL-17 upon antigen challenge 70. Moreover, IL-23 fails to sustain IL-17 in IL-1R-deficient T cells and even TNF-α and IL-6 enhancement of IL-23-induced IL-17 is IL-1 dependent. Therefore, it is likely that there is a cascade of IL-1β-induced IL-23, as well as IL-1-induced IL-6, for Th17 differentiation 71–73. The role of IL-1β in the generation of Th17 cells is also consistent with mice deficient in IL-1Ra 73. Lacking this naturally occurring antagonist of IL-1 activity, mice spontaneously develop a rheumatoid arthritis-like disease but not in mice deficient in IL-17 72. Mice deficient in both IL-1α and IL-1β do not develop experimental autoimmune encephalomyelitis, which is thought to be due to a failure to mount a Th17 response 74. In human T cells, IL-1β-dependent Th17 differentiation is due to the intermediate production of PGE275, which is not unexpected since low concentrations of IL-1β induce COX–2 42. In human T-cells, Th17 expression induced by M. tuberculosis is IL-1β dependent 76via TLR4 stimulation.

What about the other members of the IL-1F?

There are 11 members of the IL-1F of ligands (Table 1). The most recent addition is IL-33, which is the ligand for the former orphan receptor ST2 77. IL-33 plays a role in mast cell functions and drives Th2 responses. However, as noted above in the section IL-1 family (IL-1F) and evolution, the IL-33 precursor can function not only via its specific cell surface receptor but also as a DNA binding nuclear factor 35, 36. Nevertheless, neutralization of endogenous IL-33 with soluble receptors to ST2 has been studied in animal models and reduces inflammation 78, 79. IL–1F6, IL-1F8 and IL-1F9 each bind to the IL-1Rrp2 and recruit IL-1RAcP. As such, these members of the IL-1F are pro-inflammatory; the specific receptor antagonist is IL-1F5 as IL-1F5 binds to the IL-1Rrp2 but, like IL-1Ra, does not recruit the IL-1RAcP. Overexpression of IL-1F6 in the skin induces a robust inflammatory response, which is reduced by IL-1F5 80. IL-1F6 also inhibits adipocyte differentiation and induces insulin resistance.

Table 1. The IL-1 family
New nameOther nameReceptorCo-receptorProperty
  1. a

    n.a. not applicable.

IL-1F1IL-1αIL-1RIIL-1RAcPPro-inflammatory
IL-1F2IL-1βIL-1RIIL-1RAcPPro-inflammatory
IL-1F3IL-1RaIL-1RIn.a.Receptor antagonist (IL-1α; IL-1β)
IL-1F4IL-18IL-18RαIL-18RβPro-inflammatory
IL-1F5FIL1δIL-1Rrp2n.a.Receptor antagonist (IL-1F6, 8, 9)
IL-1F6FIL-1εIL-1Rrp2IL-1RAcPPro-inflammatory
IL-1F7IL-1H4IL-18RαUnknownAnti-inflammatory
IL-1F8IL-1H2IL-1Rrp2IL-1RAcPPro-inflammatory
IL-1F9IL-1εIL-1Rrp2IL-1RAcPPro-inflammatory
IL-1F10IL-1Hy2UnknownUnknownReceptor antagonist (?)
IL-1F11IL-33ST2IL-1RAcPTh2 responses

In human and animal studies, IL-18 is clearly a pro-inflammatory cytokine as reviewed in 81. Similar to IL-1β, IL-18 is first synthesized as an inactive precursor and requires caspase-1 for processing and secretion of the active cytokine. However, unlike IL-1β, the IL-18 precursor is present in most cells from healthy humans. The IL-18 binding protein is a naturally occurring protein 82 found in the circulation with a high affinity for IL-18 and hence serves as the natural inhibitor of IL-18. IL-18BP has been tested in humans with rheumatoid arthritis 83. Blocking IL-18 with IL-18BP will likely be part of the future of this member of the IL-1F, particularly in acute diseases such as macrophage activation syndrome 84 or acute renal failure 85.

IL-1F7 is a unique anti-inflammatory cytokine similar in function to IL-10 and TGF-β. However, IL-1F7 is also similar to IL-1α and IL-33 in that it translocates to the nucleus 86. Data suggest that IL-1F7 binds to the IL-18Rα 87 and, for its anti-inflammatory properties, likely recruits an accessory receptor chain with inhibitory properties, such as the single Ig IL-1 related receptor. Although IL-1F7 contains two putative caspase-1 sites, it is unclear whether IL-1F7 requires caspase-1 for activity 88 or being similar to IL-1α and IL-33, is active as a precursor.

Concluding remarks

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
  7. Supporting Information

The story of IL-1 began with the search for the endogenous fever-producing molecule; today IL-1 is a prominent member of the expanding field of cytokines. As the story unfolded over 60 years ago, few envisioned that IL-1 was a member of an entire family of pro-inflammatory molecules and certainly no one imagined that single amino acid mutations in an intracellular protein would result in debilitating inflammatory diseases. When the IL-1 receptor was studied for its unique cytosolic sequence, the TIR domain, an unexpected duplication in evolution was revealed, as receptor signaling by the IL-1F, as well as the large numbers of bacterial products and viral genes, depended on the same domain. Thus, nature insured that the innate immune response was well preserved in receptors for microbial products and for the IL-1F. Indeed, raising body temperature during infection is a survival event in lizards and fish 89; however, despite the host defense function of IL-1, the future direction for the IL-1F of ligands and receptors will likely be focused on blocking therapies for both uncommon and common inflammatory diseases, a clinical reality ushered in 25 years ago with the isolation of the cDNA for IL-1α and IL-1β.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
  7. Supporting Information

Supported by NIH Grants AI-15614, CA-04 6934 and JDRF 26-2008-893 (to C. A. D.).

Conflict of interest: The author declares no financial or commercial conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
  7. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Concluding remarks
  5. Acknowledgements
  6. References
  7. Supporting Information

See accompanying article: All Viewpoint articles

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