Inflammation in Human Disease: Anticytokine Therapy (2009)

Cytokines affect nearly every biological process, including embryonic development, disease pathogenesis, nonspecific response to infection, specific antigen responses, changes in cognitive function, and progression of the degenerative aging processes. In addition, cytokines play roles in stem cell differentiation, vaccine efficacy, and allograft rejection. This affect on multiple biological properties, or pleiotropism, is the hallmark of a cytokine. This report provides an overview of the failures and successes of cytokines as therapeutic targets. A recent advance is differential cytokine production, which can be used to classify human disease as being “autoimmune” or “autoinflammatory” and thereby guide therapeutic interventions. Cytokines wreak havoc with the immune system, turning the system against itself in autoimmune diseases. During infection, the cytokine “storm” subsides as the infection is eliminated and the genes return to their normal state of repression by histone acetylases. When the cytokine genes fail to shut down, their products drive the host into a state of chronically activated cells, which now dominate an otherwise resting immune system. Autoreactive T cells are cells that persist and fail to die. Other genetically influenced “failure to die” mechanisms likely contribute to this persistence as well. Most anticytokine therapies for autoimmune disease target the effects of cytokines on inflammatory and tissue remodeling processes but seem unable to shut down the persistently activated autoreactive T cells. The use of agents that specifically block the activity of a cytokine truly defines the role of that cytokine in disease or in an immunologic response. Although the blocking of cytokines in animal models with neutralizing strategies has established the importance of cytokines in the pathogenesis or progression of disease, approval for the use of these agents in humans remains the ultimate goal. The same agents that failed in clinical trials for sepsis were tested in patients with rheumatoid arthritis, Crohn's disease, and plaque psoriasis. In the case of blocking tumor necrosis factor (TNF)-α, monoclonal antibodies to TNF-α and soluble TNF receptors have been highly successful in treating these autoimmune diseases, having been used in more than 800,000 patients. As a result, nearly every anticytokine agent, whether an orally active inhibitor of a cytokine-regulated intracellular pathway, a neutralizing antibody, a soluble receptor, or a receptor antagonist, has been tested in patients with rheumatoid arthritis, Crohn's disease, or psoriasis. Blocking of interleukin (IL)-1, IL-6, IL-12, and IL-23 has been successful, whereas blocking of IL-15 or IL-18 has been marginal. In general, animal models can predict which cytokines are likely to improve rheumatoid arthritis and Crohn's disease [1Kosiewicz M.M. Nast C.C. Krishnan A. et al.Th1-type responses mediate spontaneous ileitis in a novel murine model of Crohn's disease.J Clin Invest. 2001; 107: 695-702Crossref PubMed Scopus (217) Google Scholar] but cannot predict which anticytokine will be efficacious for a specific patient. Autoimmune diseases included both dysfunctional immune responses and a prominent inflammatory component. Other chronic diseases appear to be mostly inflammatory in nature and associated with dysregulation of IL-1β processing and secretion. These diseases are designated autoinflammatory to distinguish them from autoimmune diseases. Examples of autoinflammatory diseases include familial Mediterranean fever, neonatal-onset multiple system inflammatory disease, and systemic-onset juvenile idiopathic arthritis. Patients with these diseases suffer from chronic fever, systemic inflammation, and joint pain. Rapid reversal of disease severity occurs after the blocking of IL-1β activity. The pathological abnormality in autoinflammatory diseases appears to be a failure to control IL-1β processing and secretion. Release of active IL-1β from blood monocytes is increased in patients with these diseases. The processing and secretion of IL-1β is controlled by caspase-1, an intracellular cysteine protease that cleaves the IL-1β precursor, as well as IL-18 and IL-33 precursors, into active cytokines. Caspase-1 is controlled by the caspsase-1 inflammasome, a complex of intracellular proteins. The discovery of inflammasomes is one of the hallmarks of cytokine biology; inflammasome-mediated processing regulates the inflammation mediated by IL-1β, IL-18, and IL-33. Most cytokines function solely by binding to specific cell surface receptors, which initiates a cascade of intracellular signals affecting gene expression mediated by transcription factors, such as nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and activator protein 1 (AP-1). Increasing evidence indicates that some cytokines function as classic ligands for specific receptors and also have another life as transcription factors; for example, the N-terminal amino acids of the IL-1β precursor binds to DNA and participates in transcriptional machinery [2Werman A. Werman-Venkert R. White R. et al.The precursor form of IL-1a is an intracrine proinflammatory activator of transcription.Proc Natl Acad Sci U S A. 2004; 101: 2434-2439Crossref PubMed Scopus (306) Google Scholar], whereas the carboxyl domain (mature) binds to the IL-1 cell surface receptor and induces the same portfolio of genes as IL-1β does. High-mobility group B-1 (HMGB-1), a nuclear DNA-binding protein that regulates gene transcription and steroid hormone receptors, binds to the receptor for advanced glycation endproducts (RAGE) and functions as a proinflammatory cytokine, inducing IL-1β and TNF-α [3Wang H. Bloom O. Zhang M. et al.HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999; 285: 248-251Crossref PubMed Scopus (2976) Google Scholar]. Antibodies to HMGB-1 reduce disease severity in animal models of inflammation. It is likely that the original functions of these immune and inflammatory responses were in signaling, but these cytokines appear to have other functions as well. For example, IL-33, the specific ligand for the IL-1 family receptor ST2, is a Th2 cytokine; however, IL-33 is homologous to the nuclear factor high endothelial venules (NF-HEVs) binding chromatin [4Carriere V. Roussel L. Ortega N. et al.IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo.Proc Natl Acad Sci U S A. 2007; 104: 282-287Crossref PubMed Scopus (791) Google Scholar]. Chromatin binding and transcriptional repression are due to the N-terminal domains of IL-33, whereas the C-terminal part of the molecule is homologous to IL-1. Interferon (IFN)-γ has intracellular targets. There is no dearth of reports on the association between circulating cytokines and disease severity. Despite highly statistically significant correlations, an important lesson in cytokine biology is that a causative role of a particular cytokine in disease can be established only by specific blockade in animals or humans. For example, serum IL-6 levels often correlate with mortality in patients with septic shock, but the administration of high doses of IL-6 to humans does not affect blood pressure or the other physiological parameters of shock. On the other hand, nanogram-per-kg doses of IL-1 or TNF-α injected into humans induces life-threatening hypotension [5Smith J.W. Longo D. Alford W.G. et al.The effects of treatment with interleukin-1a on platelet recovery after high-dose carboplatin.N Engl J Med. 1993; 328: 756-761Crossref PubMed Scopus (130) Google Scholar], yet few studies have attempted to correlate serum levels of IL-1 or TNF-α with any disease. In the past decade, another property of cytokines has emerged—their action as both an extracellular molecule engaging its specific cell surface receptor and an integral membrane protein that uses a juxtacrine mechanism of cell–cell contact for its activity [6Kaplanski G. Farnarier C. Kaplanski S. et al.Interleukin-1 induces interleukin-8 from endothelial cells by a juxacrine mechanism.Blood. 1994; 84: 4242-4248PubMed Google Scholar]. For example, a considerable amount of the biological activity of TNF-α in rheumatoid arthritis and Crohn's disease likely is mediated by membrane TNF-α. It is likely that many of the effects of cytokines occur in the microenvironment [7Apte R.N. Douvdevani A. Zoller M. et al.Cytokine-induced tumorogenicity: endogenous interleukin-1a expressed by fibrosarcoma cells confers reduced tumorogenicity.Immunol Lett. 1993; 39: 45-52Crossref PubMed Scopus (36) Google Scholar], whereas systemic levels of cytokines, such as IL-6, are primarily markers of disease severity. As more cytokines were discovered, it became clear that some cytokines had proinflammatory properties and others inhibited inflammation. The message was that nature has provided mechanisms to limit or balance exuberant cytokine responses. For example, soluble receptors [8Engelmann 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 Chem. 1990; 265: 1531-1536Abstract Full Text PDF PubMed Google Scholar, 9Girardin E. Roux-Lombard P. Grau G.E. et al.Imbalance between tumor necrosis factor a and soluble TNF receptor concentrations in severe meningococcemia.Immunology. 1992; 76: 20-23PubMed Google Scholar] and decoy receptors [10Colotta F. Dower S.K. Sims J.E. et al.The type II “decoy” receptor: a novel regulatory pathway for interleukin-1.Immunol Today. 1994; 15: 562-566Abstract Full Text PDF PubMed Scopus (336) Google Scholar] limit the cytokine action of their respective ligands. Cytokines with anti-inflammatory and immunosuppressive properties include IL-4, IL-10, IL-22, and transforming growth factor β. Even IL-6 appears to reduce inflammation; IL-6–deficient mice exhibit greater inflammation produce higher levels of TNF-α than wild-type mates. Toll-like receptor agonists induce both proinflammatory and antiinflammatory cytokines, and IL-10–deficient mice develop spontaneous inflammatory bowel disease. Mice deficient in IL-1 receptor antagonist spontaneously develop inflammatory arthritis and arteritis [11Horai R. Saijo S. Tanioka H. et al.Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist–deficient mice.J Exp Med. 2000; 191: 313-320Crossref PubMed Scopus (623) Google Scholar]; without this antagonist, these mice have no counterbalance against the effects of IL-1β. Another mechanism for controlling inflammation or during an immune response is suppression of cytokine signaling (SOCS). Increased inflammation and immune responses are observed in the absence of these gene products. But perhaps the most common mechanism for controlling runaway immune stimulation or inflammation is the effect of prostaglandins on cytokine production and cytokine activity. Prostaglandin E (PGE) 2 is perhaps the most potent suppressor of T cell function; PGE2-induced cyclic adenosine monophosphate inhibits the production of IL-2, IFN-γ, TNF-α, and other cytokines. Many persons routinely use aspirin and other inhibitors of cyclo-oxygenase (COX)-1 or -2, which affect cytokine responses, particularly immune responses. A short course of daily aspirin increases the production of IFN-γ from primary human blood T cells [12Netea M.G. Puren A.J. Dinarello C.A. A short course of oral aspirin increases IL-18–induced interferon-gamma production in whole blood cultures.Eur Cytokine Netw. 2000; 11: 379-382PubMed Google Scholar]. In contrast, PGE2 augments the production of IL-6. Oral COX inhibitors reduce serum IL-6 and acute-phase proteins in patients with rheumatoid arthritis. The discovery that nutritional status and the balance between cell membrane composition of N-3 and N-6 fatty acids affect cytokine production and activity [13Endres S. Ghorbani R. Kelley V.E. et al.The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells.N Engl J Med. 1989; 320: 265-271Crossref PubMed Scopus (1710) Google Scholar] likely explains the large body of epidemiologic evidence on the dietary affects on health, disease, and the aging process. Financial disclosure: The authors have nothing to disclose.