0
Impact of Basic Research on Tomorrow's Medicine |

Proinflammatory Cytokines* FREE TO VIEW

Charles A. Dinarello, MD
Author and Funding Information

*From the from Department of Medicine, Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Charles A. Dinarello, MD, University of Colorado Health Sciences Center, Division of Infectious Diseases, B168, 4200 East Ninth Ave, Denver, CO 80262



Chest. 2000;118(2):503-508. doi:10.1378/chest.118.2.503
Text Size: A A A
Published online

Study objectives: To review the concept of proinflammatory cytokines.

Design: Review of published literature.

Setting: Academic (university hospital).

Results: Cytokines are regulators of host responses to infection, immune responses, inflammation, and trauma. Some cytokines act to make disease worse (proinflammatory), whereas others serve to reduce inflammation and promote healing (anti-inflammatory). Attention also has focused on blocking cytokines, which are harmful to the host, particularly during overwhelming infection. Interleukin (IL)-1 and tumor necrosis factor (TNF) are proinflammatory cytokines, and when they are administered to humans, they produce fever, inflammation, tissue destruction, and, in some cases, shock and death. Reducing the biological activities of IL-1 and TNF is accomplished by several different, but highly specific, strategies, which involve neutralizing antibodies, soluble receptors, receptor antagonist, and inhibitors of proteases that convert inactive precursors to active, mature molecules. Blocking IL-1 or TNF has been highly successful in patients with rheumatoid arthritis, inflammatory bowel disease, or graft-vs-host disease but distinctly has not been successful in humans with sepsis. Agents such as TNF-neutralizing antibodies, soluble TNF receptors, and IL-1 receptor antagonist have been infused into > 10,000 patients in double-blind, placebo-controlled trials. Although there has been a highly consistent small increase (2 to 3%) in 28-day survival rates with anticytokine therapy, the effect has not been statistically significant.

Conclusions: Anticytokine therapy should be able to“ rescue” the patient whose condition continues to deteriorate in the face of considerable support efforts. Unfortunately, it remains difficult to identify those patients who would benefit from anticytokine therapy for septic shock.

Figures in this Article

Cytokines are small, nonstructural proteins with molecular weights ranging from 8 to 40,000 d. Originally called lymphokines and monokines to indicate their cellular sources, it became clear that the term “cytokine” is the best description, since nearly all nucleated cells are capable of synthesizing these proteins and, in turn, of responding to them. There is no amino acid sequence motif or three-dimensional structure that links cytokines; rather, their biological activities allow us to group them into different classes. For the most part, cytokines are primarily involved in host responses to disease or infection, and any involvement with homeostatic mechanisms has been less than dramatic.

Many scientists have made the analogy of cytokines to hormones, but, on closer examination, this is not an accurate comparison. Why? First, hormones tend to be constitutively expressed by highly specialized tissues, but cytokines are synthesized by nearly every cell. Whereas hormones are the primary synthetic product of a cell (insulin, thyroid, adrenocorticotropic hormone, etc), cytokines account for a rather small amount of the synthetic output of a cell. In addition, hormones are expressed in response to homeostatic control signals, many of which are part of a daily cycle. In contrast, most cytokine genes are not expressed (at least at the translational level) unless specifically stimulated by noxious events. In fact, it has become clear that the triggering of cytokine gene expression is nearly identical to “cell stressors.” For example, ultraviolet light, heat-shock, hyperosmolarity, or adherence to a foreign surface activate the mitogen-activated protein kinases (MAPKs), which phosphorylate transcription factors for gene expression. Of course, infection and inflammatory products also use the MAPK pathway for initiating cytokine gene expression. One concludes then that cytokines themselves are produced in response to “stress,” whereas most hormones are produced by a daily intrinsic clock.

There are presently 18 cytokines with the name interleukin (IL). Other cytokines have retained their original biological description, such as tumor necrosis factor (TNF). Another way to look at some cytokines is their role in infection and/or inflammation. Some cytokines clearly promote inflammation and are called proinflammatory cytokines, whereas other cytokines suppress the activity of proinflammatory cytokines and are called anti-inflammatory cytokines. For example, IL-4, IL-10, and IL-13 are potent activators of B lymphocytes. However, IL-4, IL-10, and IL-13 are also potent anti-inflammatory agents. They are anti-inflammatory cytokines by virtue of their ability to suppress genes for proinflammatory cytokines such as IL-1, TNF, and the chemokines.

Interferon (IFN)-γ is another example of the pleiotropic nature of cytokines. Like IFN-α and IFN-β, IFN-γ possesses antiviral activity. IFN-γ is also an activator of the pathway that leads to cytotoxic T cells. However, IFN-γ is considered a proinflammatory cytokine because it augments TNF activity and induces nitric oxide (NO). Therefore, listing cytokines in various categories should be done with an open mind, in that, depending on the biological process, any cytokine may function differentially.

The concept that some cytokines function primarily to induce inflammation while others suppress inflammation is fundamental to cytokine biology and also to clinical medicine. The concept is based on the genes coding for the synthesis of small mediator molecules that are up-regulated during inflammation. For example, genes that are proinflammatory are type II phospholipase (PL) A2, cyclooxygenase (COX)-2, and inducible NO synthase. These genes code for enzymes that increase the synthesis of platelet-activating factor and leukotrienes, prostanoids, and NO. Another class of genes that are proinflammatory are chemokines, which are small peptides (8,000 d) that facilitate the passage of leukocytes from the circulation into the tissues. The prototypical chemokine is the neutrophil chemoattractant IL-8. IL-8 also activates neutrophils to degranulate and cause tissue damage. IL-1 and TNF are inducers of endothelial adhesion molecules, which are essential for the adhesion of leukocytes to the endothelial surface prior to emigration into the tissues. Taken together, proinflammatory cytokine-mediated inflammation is a cascade of gene products usually not produced in healthy persons. What triggers the expression of these genes? Although inflammatory products such as endotoxins trigger it, the cytokines IL-1 and TNF (and in some cases IFN-γ) are particularly effective in stimulating the expression of these genes. Moreover, IL-1 and TNF act synergistically in this process. Whether induced by an infection, trauma, ischemia, immune-activated T cells, or toxins, IL-1 and TNF initiate the cascade of inflammatory mediators by targeting the endothelium. Figure 1 illustrates the inflammatory cascade triggered by IL-1 and TNF.

Anti-inflammatory cytokines block this process or at least suppress the intensity of the cascade. Cytokines such as IL-4, IL-10, IL-13, and transforming growth factor (TGF)-β suppress the production of IL-1, TNF, chemokines such as IL-8, and vascular adhesion molecules. Therefore, a “balance” between the effects of proinflammatory and anti-inflammatory cytokines is thought to determine the outcome of disease, whether in the short term or long term. In fact, some studies have data suggesting that susceptibility to disease is genetically determined by the balance or expression of either proinflammatory or anti-inflammatory cytokines. However, gene linkage studies are often difficult to interpret. Nevertheless, the deletion of the IL-10 gene in mice results in the spontaneous development of a fatal inflammatory bowel disease. Deletion of the TGF-β1 gene also results in a spontaneous inflammatory disease. In mice deficient in IL-1 receptor antagonist (IL-Ra), spontaneous disease that is nearly identical to rheumatoid arthritis is observed.

The synergism of IL-1 and TNF is a commonly reported phenomenon. Clearly, both cytokines are being produced at sites of local inflammation, and, hence, the net effect should be considered when making correlations between cytokine levels and severity of disease. There is also synergism between IL-1 and bradykinin as well as between IL-1 or TNF and mesenchymal growth factors. Most relevant to pain is the increase in prostaglandin (PG)-E2 stimulated by IL-1 or the combination of IL-1 and TNF. IL-1 also lowers the threshold of pain primarily by increasing PGE2 synthesis.1Table 1 summarizes the synergism of IL-1 and TNF.

Humans injected with IL-1 experience fever, headache, myalgias, and arthralgias, each of which is reduced by the coadministration of COX inhibitors.2 One of the more universal activities of IL-1 is the induction of gene expression for type II PLA2 and COX-2. IL-1 induces the transcription of COX-2 and seems to have little effect on the increased production of COX-1. Moreover, once triggered, COX-2 production is elevated for several hours and large amounts of PGE2 are produced in cells stimulated with IL-1. Therefore, it comes as no surprise that many biological activities of IL-1 are actually due to increased PGE2 production. There appears to be selectivity in COX inhibitors, in that some nonsteroidal anti-inflammatory agents are better inhibitors of COX-2 than of COX-1. Similar to COX-2 induction, IL-1 preferentially stimulates new transcripts for the inducible type II form of PLA2, which cleaves the fatty acid in the number 2 position of cell membrane phospholipids. In most cases, this is arachidonic acid. The release of arachidonic acid is the rate-limiting step in the synthesis of PGs and leukotrienes. IL-1 also stimulates increased leukotriene synthesis in many cells.

Receptors

Two primary IL-1 binding proteins (IL-1 receptors [IL-1Rs]) and one IL-1R accessory protein (IL-1R-AcP) have been identified.34 The extracellular domains of the two IL-1Rs and the IL-1R-AcP are members of the Ig superfamily, are each composed of three IgG-like domains, and share a significant homology to each other. The two IL-1Rs are distinct gene products, and, in humans, the genes for type I IL-1R (IL-1RI) and type II IL-1R (IL-1RII) are located on the long arm of chromosome 2.5

In primary cells, there are < 50 IL-1Rs per cell, and IL-1 signal transduction has been observed in cells expressing < 10 IL-1RIs per cell. Interestingly, the cytosolic domain of IL-1RI has a 45% amino acid homology with the cytosolic domain of the Drosophila Toll gene.6Toll is a transmembrane protein that acts like a receptor. There are several mammalian receptors called Toll-like receptors (TLRs). The ligands for two of these are endotoxin (TLR-4)7and peptidoglycan (TLR-2). The cytoplasmic domains of the TLR are nearly identical to those of IL-1 and IL-18.8Gene organization and amino acid homology suggest that the IL-1RI and the cytosolic Toll are derived from a common ancestor (Toll) and trigger similar signals.9

Like other models of two-chain receptors, IL-1 binds first to the IL-1RI with a low affinity. The crystal structure of the IL-1RI complexed with IL-1β has been reported and sheds light on the changes that take place after the low-affinity binding.10 The two receptor-binding sites of IL-1β have been reported using specific mutations. The crystal structure reveals that both receptor-binding sites contact the IL-1RI at the first and third domains.10 On contact with the first domain, there appears to be a change in the rigidity of the third domain to encounter contact with the second binding site of IL-1β. IL-1β itself does not undergo a structural change. IL-1Ra has only one binding site,11and its absence prevents contact with the third domain. Hence, the critical contact point appears to be at the third domain. Since this contact is likely to be absent in complexes with the IL-1Ra,12 the structural change in the IL-1RI third domain may allow docking of the IL-1R-AcP with the IL-1RI/IL-1β complex. Without the complex of IL-1R-AcP/IL-1RI/IL-1β, there is no signal transduction.4

Antibodies to IL-1RI and IL-1R-AcP block IL-1 binding and activity.4 IL-1R-AcP is essential to IL-1 signaling; in cells deficient in IL-1R-AcP, no IL-1-induced activation of the stress kinases takes place, but this response is restored on transfection with a construct expressing IL-1R-AcP.13Affinity-purified antibodies to the IL-1R-AcP third domain amino acids preferentially block IL-1β activity,14 suggesting that the docking of IL-1R-AcP with IL-1RI takes place within the third domain of each receptor.

IL-1 Decoy Receptor

IL-1RII has a short cytosolic domain consisting of 29 amino acids. IL-1RII appears to act as “decoy” molecule, particularly for IL-1β. The receptor binds IL-β tightly, thus preventing binding to the signal-transducing IL-1RI.15 It is the lack of a signal-transducing cytosolic domain that makes IL-1RII a functionally negative receptor.

Signal Transduction

Within a few minutes following binding to cells, IL-1 induces several biochemical events.1619 It remains unclear which is the most “upstream” triggering event or whether several events occur at the same time. No sequential order or cascade has been identified, but several signaling events appear to be taking place during the first 2 to 5 min. Some of the biochemical changes associated with signal transduction are likely to be cell-specific. In general, multiple protein phosphorylations and activation of phosphatases can be observed within 5 min,20and some are thought to be initiated by the release of lipid mediators. The release of ceramide has attracted attention as a possible early signaling event.21Phosphorylation of PLA2 activating protein (AP) also occurs in the first few minutes,22 which leads to a rapid release of arachidonic acid. Multiple and similar signaling events also have been reported for TNF.

With few exceptions, there is general agreement that IL-1 does not stimulate either hydrolysis of phosphatidylinositol or an increase in intracellular calcium. Without a clear increase in intracellular calcium, early postreceptor binding events nevertheless include hydrolysis of a guanosine 5′-triphosphate with no associated increase in adenyl cyclase, activation of adenyl cyclase,2324 hydrolysis of phospholipids,2526 release of ceramide,27 and release of arachidonic acid from phospholipids via cytosolic PLA2 following its activation by PLA2 AP.,22 Some IL-1 signaling events are prominent in different cells. Postreceptor signaling mechanisms may, therefore, provide cellular specificity. For example, in some cells, IL-1 is a growth factor, and signaling is associated with serine/threonine phosphorylation of the MAPK p42/44 in mesangial cells.28The MAPK p38, another member of the MAPK family, is phosphorylated in fibroblasts,29as is the p54α MAPK in hepatocytes.30

IL-1-induces several transcription factors. Most of the biological effects of IL-1 take place in cells following nuclear translocation of nuclear factor (NF)-κB and AP-1, two NFs that are common to many IL-1-induced genes. In T lymphocytes and cultured hepatocytes, the addition of IL-1 increases the nuclear binding of c-jun and c-fos, the two components of AP-1.31Similar to those for NF-κB, AP-1 sites are present in the promoter regions of many IL-1-inducible genes. IL-1 also increases the transcription of c-jun by activating two novel NFs (jun-1 and jun-2) that bind to the promoter of the c-jun gene and stimulate c-jun transcription.32

How Does IL-1 Differ From TNF in Activating Cells?

From the above descriptions of IL-1R and IL-1 signal transduction, we can see that many of these pathways are shared with TNF. Although the receptors for TNF and IL-1 are clearly different, the postreceptor events are amazingly similar. Thus, the finding that IL-1 and TNF activate the same portfolio of genes is not surprising. However, given the same cell and given the same array of activated genes, IL-1 does not result in programmed cell death, whereas TNF does. This can be seen in TNF-responsive fibroblasts in which IL-1 and TNF induce IL-8 but in the presence of actinomycin or cycloheximide, but in which TNF induces classic apoptosis but IL-1 does not. IL-1 will often synergize with TNF for NO induction, and, under those conditions, NO mediates cell death. The best example of this can be found in the insulin-producing β cells in the islets of Langerhans in the pancreas.33Unlike IL-1, the receptors for TNF are homodimers and trimers, and, hence, the recruitment of kinases is somewhat different. However, the cytosolic domain of the TNF p55 receptor contains a “death domain” that recruits intracellular molecules involved with initiating programmed cell death.34 There is no comparable death domain in the cytoplasmic domains of either IL-1RI or IL-1R-AcP.

There are two receptors for TNF, the p55 receptor and the p75 receptor.35 Although TNF binds and triggers both receptors, the cytosolic domains of these receptors recruit different proteins that transduce the TNF signal further. In one case, the p55 receptor cytosolic domain is linked to pathways of cell death, whereas the p75 is not. Both receptors, however, result in the translocation of the NF-κB to the nucleus, where it binds to the promoter regions of a variety of genes. These gene products are often the same as those triggered by IL-1, which also results in the translocation of NF-κB to the nucleus. The difference is, however, that the cytosolic domains of the p55 TNF receptor (TNFR) are unique in their ability to activate intracellular signals leading to programmed cell death (also called apoptosis). The p55 TNFR has the so-called death domain and recruits a protein called MORT-1. Also involved in this process is a family of intracellular proteins that becomes activated; these proteins are called TNFR-associated factors. Presently there are six or perhaps eight TNFR-associated factors. The p55 cytosolic domains also recruit the family of intracellular proteins called TNFR-associated death domains (TRADDs). The overexpression of TRADDs results in cell death. It also leads to activation of NF-κB. TRADDs also lead to the activation of the caspase family of intracellular cysteine proteases. Although caspase-1 (also knows as the IL-1β-converting enzyme) is important for processing the precursors for proIL-1β and proIL-18, other members of this family are also part of the TNF cell death signaling pathway.

One interesting aspect of the biology of TNF in the brain is its ability to both protect neurons as well as to initiate their self-destruction. Both pathways involve the activation of NF-κB.36 In general, the state of the cell (cell cycle) may help to explain why the activation of NF-κB can be associated with both the protection of cell death as well as apoptosis. One is reminded that the activation of NF-κB leads most often to new protein synthesis; some proteins from this process are clearly inducing cell proliferation, whereas others induce cell death.

Abbreviations: AP = activating protein; COX = cyclooxygenase; IFN = interferon; IL = interleukin; IL-1R = interleukin-1 receptor; IL-1RI = type I interleukin-1 receptor; IL-1Ra = interleukin-1 receptor antagonist; IL-1RII = type II interleukin-1 receptor; IL-1R-AcP = interleukin-1 receptor accessory protein; MAPK = mitogen-activated protein kinase; NF = nuclear factor; NO = nitric oxide; PG = prostaglandin; PL = phospholipase; RA = receptor antagonist; TGF = transforming growth factor; TLR = Toll-like receptor; TNF = tumor necrosis factor; TNFR = tumor necrosis factor receptor; TRADD = tumor necrosis factor receptor-associated death domain

Supported by National Institutes of Health Grant AI-15614.

Figure Jump LinkFigure 1. The inflammatory cascade triggered by IL-1 and TNF. iNOS = inducible NO synthase; PAF = platelet-activating factor.Grahic Jump Location
Table Graphic Jump Location
Table 1. Synergistic Activities of IL-1 and TNF*
* 

FGF = fibroblast growth factor; EGF = epidermal growth factor; PDGF = platelet-derived growth factor.

Schweizer, A, Feige, U, Fontana, A, et al (1988) Interleukin-1 enhances pain reflexes: mediation through increased prostaglandin E2 levels.Agents Actions25,246-251. [CrossRef] [PubMed]
 
Smith, JW, Urba, WJ, Curti, BD, et al Phase II trial of interleukin-1 alpha in combination with indomethacin in melanoma patients [abstract]. Proc Am Soc Clin Oncol Annu Meet. 1991;;10 ,.:293
 
Sims, JE, Giri, JG, Dower, SK The two interleukin-1 receptors play different roles in IL-1 activities.Clin Immunol Immunopathol1994;72,9-14. [CrossRef] [PubMed]
 
Greenfeder, SA, Nunes, P, Kwee, L, et al Molecular cloning and characterization of a second subunit of the interleukin-1 receptor complex.J Biol Chem1995;270,13757-13765. [CrossRef] [PubMed]
 
Sims, JE, Painter, SL, Gow, IR Genomic organization of the type I and type II IL-1 receptors.Cytokine1995;7,483-490. [CrossRef] [PubMed]
 
Gay, NJ, Keith, FJ DrosophilaTolland IL-1 receptor.Nature1991;351,355-356. [PubMed]
 
Du, X, Thompson, P, Chan, EKL, et al Genetic and physical mapping of the Lps locus: identification of the Toll-4 receptor as a candidate gene in the critical region.Blood Cells Mol Dis1998;24,340-355. [CrossRef] [PubMed]
 
Dinarello, CA IL-18: a Th1-inducing, proinflammatory cytokine and new member of the IL-1 family.J Allergy Clin Immunol1999;103,11-24. [CrossRef] [PubMed]
 
Heguy, A, Baldari, CT, Macchia, G, et al Amino acids conserved in interleukin-1 receptors and the DrosophilaTollprotein are essential for IL-1R signal transduction.J Biol Chem1992;267,2605-2609. [PubMed]
 
Vigers, GPA, Anderson, LJ, Caffes, P, et al Crystal structure of the type I interleukin-1 receptor complexed with interleukin-1β.Nature1997;386,190-194. [CrossRef] [PubMed]
 
Evans, RJ, Bray, J, Childs, JD, et al Mapping receptor binding sites in the IL-1 receptor antagonist and IL-1β by site-directed mutagenesis: identification of a single site in IL-1ra and two sites in IL-1β.J Biol Chem1994;270,11477-11483
 
Schreuder, H, Tardif, C, Trump-Kallmeyer, S, et al A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist.Nature1997;386,194-200. [CrossRef] [PubMed]
 
Wesche, H, Korherr, C, Kracht, M, et al The interleukin-1 receptor accessory protein is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases).J Biol Chem1997;272,7727-7731. [CrossRef] [PubMed]
 
Yoon, DY, Dinarello, CA Antibodies to domains II and III of the IL-1 receptor accessory protein inhibit IL-1β activity but not binding: regulation of IL-1 responses is via type I receptor, not the accessory protein.J Immunol1998;160,3170-3179. [PubMed]
 
Colotta, F, Re, F, Muzio, M, et al Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.Science1993;261,472-475. [CrossRef] [PubMed]
 
O’Neill, LAJ Towards an understanding of the signal transduction pathways for interleukin-1.Biochim Biophys Acta1995;1266,31-44. [CrossRef] [PubMed]
 
Mizel, SB IL-1 signal transduction.Eur Cytokine Netw1994;5,547-561. [PubMed]
 
Rossi, B IL-1 transduction signals.Eur Cytokine Netw1993;4,181-187. [PubMed]
 
Kuno, K, Matsushima, K The IL-1 receptor signaling pathway.J Leukoc Biol1994;56,542-547. [PubMed]
 
Bomalaski, JS, Steiner, MR, Simon, PL, et al IL-1 increases phospholipase A2 activity, expression of phospholipase A2-activating protein, and release of linoleic acid from the murine T helper cell line EL-4.J Immunol1992;148,155-160. [PubMed]
 
Kolesnick, R, Golde, DW The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signalling.Cell1994;77,325-328. [CrossRef] [PubMed]
 
Gronich, J, Konieczkowski, M, Gelb, MH, et al Interleukin-1α causes a rapid activation of cytosolic phospholipase A2 by phosphorylation in rat mesangial cells.J Clin Invest1994;93,1224-1233. [CrossRef] [PubMed]
 
Mizel, SB Cyclic AMP and interleukin-1 signal transduction.Immunol Today1990;11,390-391. [CrossRef] [PubMed]
 
Munoz, E, Beutner, U, Zubiaga, A, et al IL-1 activates two separate signal transduction pathways in T helper type II cells.J Immunol1990;144,964-969. [PubMed]
 
Kester, M, Siomonson, MS, Mene, P, et al Interleukin-1 generates transmembrane signals from phospholipids through novel pathways in cultured rat mesangial cells.J Clin Invest1989;83,718-723. [CrossRef] [PubMed]
 
Rosoff, PM, Savage, N, Dinarello, CA Interleukin-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism.Cell1988;54,73-81. [CrossRef] [PubMed]
 
Mathias, S, Younes, A, Kan, C-C, et al Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1β.Science1993;259,519-522. [CrossRef] [PubMed]
 
Huwiler, A, Pfeilschifter, J Interleukin-1 stimulatesde novosynthesis of mitogen-activated protein kinase in glomerular mesangial cells.FEBS Lett1994;350,135-138. [CrossRef] [PubMed]
 
Freshney, NW, Rawlinson, L, Guesdon, F, et al Interleukin-1 activates a novel protein cascade that results in the phosphorylation of hsp27.Cell1994;78,1039-1049. [CrossRef] [PubMed]
 
Kracht, M, Truong, O, Totty, NF, et al Interleukin-1α activates two forms of p54α mitogen-activated protein kinase in rabbit liver.J Exp Med1994;180,2017-2027. [CrossRef] [PubMed]
 
Muegge, K, Williams, TM, Kant, J, et al Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1.Science1989;246,249-251. [CrossRef] [PubMed]
 
Muegge, K, Vila, M, Gusella, GL, et al IL-1 induction of the c-jun promoter.Proc Natl Acad Sci USA1993;90,7054-7058. [CrossRef] [PubMed]
 
Reimers, JI, Bjerre, U, Mandrup-Poulsen, T, et al Interleukin-1β induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases.Cytokine1994;6,512-520. [CrossRef] [PubMed]
 
Boldin, MP, Varfolomeev, EE, Pancer, Z, et al A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.J Biol Chem1995;270,7795-7798. [CrossRef] [PubMed]
 
Engelmann, H, Novick, D, Wallach, D Two tumor necrosis factor-binding proteins purified from human urine: evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors.J Biol Chem1990;265,1531-1536. [PubMed]
 
Hunter, CA, Timans, J, Pisacane, P, et al Comparison of the effects of interleukin-1α, interleukin-1β and interferon-γ inducing factor on the production of interferon-γ by natural killer.Eur J Immunol1997;27,2787-2792. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. The inflammatory cascade triggered by IL-1 and TNF. iNOS = inducible NO synthase; PAF = platelet-activating factor.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1. Synergistic Activities of IL-1 and TNF*
* 

FGF = fibroblast growth factor; EGF = epidermal growth factor; PDGF = platelet-derived growth factor.

References

Schweizer, A, Feige, U, Fontana, A, et al (1988) Interleukin-1 enhances pain reflexes: mediation through increased prostaglandin E2 levels.Agents Actions25,246-251. [CrossRef] [PubMed]
 
Smith, JW, Urba, WJ, Curti, BD, et al Phase II trial of interleukin-1 alpha in combination with indomethacin in melanoma patients [abstract]. Proc Am Soc Clin Oncol Annu Meet. 1991;;10 ,.:293
 
Sims, JE, Giri, JG, Dower, SK The two interleukin-1 receptors play different roles in IL-1 activities.Clin Immunol Immunopathol1994;72,9-14. [CrossRef] [PubMed]
 
Greenfeder, SA, Nunes, P, Kwee, L, et al Molecular cloning and characterization of a second subunit of the interleukin-1 receptor complex.J Biol Chem1995;270,13757-13765. [CrossRef] [PubMed]
 
Sims, JE, Painter, SL, Gow, IR Genomic organization of the type I and type II IL-1 receptors.Cytokine1995;7,483-490. [CrossRef] [PubMed]
 
Gay, NJ, Keith, FJ DrosophilaTolland IL-1 receptor.Nature1991;351,355-356. [PubMed]
 
Du, X, Thompson, P, Chan, EKL, et al Genetic and physical mapping of the Lps locus: identification of the Toll-4 receptor as a candidate gene in the critical region.Blood Cells Mol Dis1998;24,340-355. [CrossRef] [PubMed]
 
Dinarello, CA IL-18: a Th1-inducing, proinflammatory cytokine and new member of the IL-1 family.J Allergy Clin Immunol1999;103,11-24. [CrossRef] [PubMed]
 
Heguy, A, Baldari, CT, Macchia, G, et al Amino acids conserved in interleukin-1 receptors and the DrosophilaTollprotein are essential for IL-1R signal transduction.J Biol Chem1992;267,2605-2609. [PubMed]
 
Vigers, GPA, Anderson, LJ, Caffes, P, et al Crystal structure of the type I interleukin-1 receptor complexed with interleukin-1β.Nature1997;386,190-194. [CrossRef] [PubMed]
 
Evans, RJ, Bray, J, Childs, JD, et al Mapping receptor binding sites in the IL-1 receptor antagonist and IL-1β by site-directed mutagenesis: identification of a single site in IL-1ra and two sites in IL-1β.J Biol Chem1994;270,11477-11483
 
Schreuder, H, Tardif, C, Trump-Kallmeyer, S, et al A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist.Nature1997;386,194-200. [CrossRef] [PubMed]
 
Wesche, H, Korherr, C, Kracht, M, et al The interleukin-1 receptor accessory protein is essential for IL-1-induced activation of interleukin-1 receptor-associated kinase (IRAK) and stress-activated protein kinases (SAP kinases).J Biol Chem1997;272,7727-7731. [CrossRef] [PubMed]
 
Yoon, DY, Dinarello, CA Antibodies to domains II and III of the IL-1 receptor accessory protein inhibit IL-1β activity but not binding: regulation of IL-1 responses is via type I receptor, not the accessory protein.J Immunol1998;160,3170-3179. [PubMed]
 
Colotta, F, Re, F, Muzio, M, et al Interleukin-1 type II receptor: a decoy target for IL-1 that is regulated by IL-4.Science1993;261,472-475. [CrossRef] [PubMed]
 
O’Neill, LAJ Towards an understanding of the signal transduction pathways for interleukin-1.Biochim Biophys Acta1995;1266,31-44. [CrossRef] [PubMed]
 
Mizel, SB IL-1 signal transduction.Eur Cytokine Netw1994;5,547-561. [PubMed]
 
Rossi, B IL-1 transduction signals.Eur Cytokine Netw1993;4,181-187. [PubMed]
 
Kuno, K, Matsushima, K The IL-1 receptor signaling pathway.J Leukoc Biol1994;56,542-547. [PubMed]
 
Bomalaski, JS, Steiner, MR, Simon, PL, et al IL-1 increases phospholipase A2 activity, expression of phospholipase A2-activating protein, and release of linoleic acid from the murine T helper cell line EL-4.J Immunol1992;148,155-160. [PubMed]
 
Kolesnick, R, Golde, DW The sphingomyelin pathway in tumor necrosis factor and interleukin-1 signalling.Cell1994;77,325-328. [CrossRef] [PubMed]
 
Gronich, J, Konieczkowski, M, Gelb, MH, et al Interleukin-1α causes a rapid activation of cytosolic phospholipase A2 by phosphorylation in rat mesangial cells.J Clin Invest1994;93,1224-1233. [CrossRef] [PubMed]
 
Mizel, SB Cyclic AMP and interleukin-1 signal transduction.Immunol Today1990;11,390-391. [CrossRef] [PubMed]
 
Munoz, E, Beutner, U, Zubiaga, A, et al IL-1 activates two separate signal transduction pathways in T helper type II cells.J Immunol1990;144,964-969. [PubMed]
 
Kester, M, Siomonson, MS, Mene, P, et al Interleukin-1 generates transmembrane signals from phospholipids through novel pathways in cultured rat mesangial cells.J Clin Invest1989;83,718-723. [CrossRef] [PubMed]
 
Rosoff, PM, Savage, N, Dinarello, CA Interleukin-1 stimulates diacylglycerol production in T lymphocytes by a novel mechanism.Cell1988;54,73-81. [CrossRef] [PubMed]
 
Mathias, S, Younes, A, Kan, C-C, et al Activation of the sphingomyelin signaling pathway in intact EL4 cells and in a cell-free system by IL-1β.Science1993;259,519-522. [CrossRef] [PubMed]
 
Huwiler, A, Pfeilschifter, J Interleukin-1 stimulatesde novosynthesis of mitogen-activated protein kinase in glomerular mesangial cells.FEBS Lett1994;350,135-138. [CrossRef] [PubMed]
 
Freshney, NW, Rawlinson, L, Guesdon, F, et al Interleukin-1 activates a novel protein cascade that results in the phosphorylation of hsp27.Cell1994;78,1039-1049. [CrossRef] [PubMed]
 
Kracht, M, Truong, O, Totty, NF, et al Interleukin-1α activates two forms of p54α mitogen-activated protein kinase in rabbit liver.J Exp Med1994;180,2017-2027. [CrossRef] [PubMed]
 
Muegge, K, Williams, TM, Kant, J, et al Interleukin-1 costimulatory activity on the interleukin-2 promoter via AP-1.Science1989;246,249-251. [CrossRef] [PubMed]
 
Muegge, K, Vila, M, Gusella, GL, et al IL-1 induction of the c-jun promoter.Proc Natl Acad Sci USA1993;90,7054-7058. [CrossRef] [PubMed]
 
Reimers, JI, Bjerre, U, Mandrup-Poulsen, T, et al Interleukin-1β induces diabetes and fever in normal rats by nitric oxide via induction of different nitric oxide synthases.Cytokine1994;6,512-520. [CrossRef] [PubMed]
 
Boldin, MP, Varfolomeev, EE, Pancer, Z, et al A novel protein that interacts with the death domain of Fas/APO1 contains a sequence motif related to the death domain.J Biol Chem1995;270,7795-7798. [CrossRef] [PubMed]
 
Engelmann, H, Novick, D, Wallach, D Two tumor necrosis factor-binding proteins purified from human urine: evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors.J Biol Chem1990;265,1531-1536. [PubMed]
 
Hunter, CA, Timans, J, Pisacane, P, et al Comparison of the effects of interleukin-1α, interleukin-1β and interferon-γ inducing factor on the production of interferon-γ by natural killer.Eur J Immunol1997;27,2787-2792. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543