Skip to main content

Interferons and Interleukins

  • Chapter
  • First Online:
Pharmaceutical Biotechnology
  • 114k Accesses

Abstract

Endogenous interferons and interleukins, major protagonists of our defense system, act in a concerted way within the immune system to defend against, contain or eliminate toxic or invasive agents. Because of their toxic effects several containment mechanisms, such as short half-life, downregulation and neutralization factors ensure that their action is strictly localized. Various diseases are accompanied by acute systemic or chronic-relapsing symptoms of inflammation. These are a sign of containement failure, i.e. dysregulation of interleukin production. During the past few years our understanding of the cellular and molecular mechanisms of immune regulation in allergy, chronic inflammatory and autoimmune diseases, tumor development, and chronic infections has grown at a rapid pace. Better insight into the functions, reciprocal regulation and antagonism of interleukins, interferons and other cytokines offer opportunities for novel treatment approaches. In the era of biological response modifier (BRM) development, targeting these molecules or their receptors appears particularly promising. Because of their toxicity, systemically administered interferons and interleukins have a number of unwanted effects. The main effort in research for their therapeutic use is therefore directed towards mitigating their toxic effects and improving their pharmacokinetic properties. These efforts have led to the development of anti-interleukin monoclonal antibodies or receptor antagonists for therapeutic use in chronic inflammatory diseases where interleukin overproduction is the culprit. On the other hand, protein engineering of interferons or therapeutic interleukins has led to improved pharmacological properties with subsequent reduction of toxicity. Other research efforts have resulted in engineered fusion protein molecules with target specificity as well as an improved pharmacologic profile.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    Reviews that summarize the referenced subject in more detail.

References

  • Aggarwal S, Ghilardi N, Xie M-H et al (2003) Interleukin-23 promotes a distinct CD4 T cell activation state characterised by the production of IL-17. J Biol Chem 278:1910–1914

    Article  CAS  Google Scholar 

  • Akdis M, Aab A, Altunbilakli C et al (2016) Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol 138(4):984–1010

    Article  CAS  Google Scholar 

  • Alfaro C, Sanmamed MF, Rodriguez ME et al (2017) Interleukin-8 in cancer pathogenesis, treatment and follow-up. Cancer Treat Rev 60:24–31

    Article  CAS  Google Scholar 

  • Algranati NE, Sy S, Modi M (1999) A branched methoxy 40-kDa polyethylene glycol (PEG) moiety optimizes the pharmacokinetics of peginterferon alpha-2a (PEG-IFN) and may explain its enhanced efficacy in chronic hepatitis C. Hepatology 40:190A

    Google Scholar 

  • Artillo S, Pastore G, Alberti A et al (1998) Double-blind, randomized controlled trial of interleukin-2 for the treatment of chronic hepatitis B. J Med Virol 54:167–172

    Article  CAS  Google Scholar 

  • Azuma YT, Matsuo Y, Kuwamura M, Yancopoulos GD, Valenzuela DM, Murphy AJ, Nakajima H, Karow M, Takeuchi T (2010) Interleukin-19 protects mice from innate-mediated colonic inflammation. Inflammatory Bowel Disease 16(6):1017–1028

    Article  Google Scholar 

  • Baud’huin M, Renault R, Charrier C et al (2010) Interleukin-34 is expressed by giant cell tumours of bone and plays a key role in RANKL-induced osteoclastogenesis. J Pathol 221:77–86

    Article  Google Scholar 

  • Bilsborough J, Leung DYM, Maurer M et al (2006) IL-31 is associated with cutaneous lymphocyte antigen-positive skin homing T cells in patients with atopic dermatitis. J Allergy Clin Immunol 117:418–425

    Article  CAS  Google Scholar 

  • Cao SG, Zhao QY, Ding ZT et al (1990) Chemical modification of enzyme molecules to improve their characteristics. Ann N Y Acad Sci 613:460–467

    Article  CAS  Google Scholar 

  • Carreño V, Zeuzem S, Hopf U et al (2000) A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis B. J Hepatol 32:317–324

    Article  Google Scholar 

  • Carreño V, Tapia L, Ryff JC et al (1992) Treatment of chronic hepatitis C by continuous subcutaneous infusion of interferon-alpha. J Med Virol 37:215–219

    Article  Google Scholar 

  • Collison LW, Workman CJ, Kuo TT, Boyd K, Wang Y, Vignali KM, Cross R, Sehy D, Costelloe C, Watson M, Murphy A, McQuillan K, Loscher C, Armstrong ME, Garlanda C, Mantovani A, O’Neill LA, Mills KH, Lynch MA (2008) IL-1F5 mediates anti-inflammatory activity in the brain through induction of IL-4 following interaction with SIGIRR/TIR8. J Neurochem 105(5):1960–1969

    Article  Google Scholar 

  • Cruikshank WW, Little F (2008) Interleukin-16: the ins and outs of regulating T-cell activation. Crit Rev Immunol 28(6):467–483

    Article  CAS  Google Scholar 

  • Dent P, Yacoub A, Hamed HA et al (2010) The development of MDA-7/IL-24 as a cancer therapeutic. Pharmacol Ther 128(2):375–384

    Article  CAS  Google Scholar 

  • Donnelly RP, Sheikh F, Dickensheets H, Savan R, Young HA, Walter MR (2010) Interleukin-26: an IL-10 related cytokine produced by Th-17 cells. Cytokine Growth Factor Rev 21(5):393–401

    Article  CAS  Google Scholar 

  • Donnelly RP, Kotenko SV (2010) Interferon-lambda: a new addition to an old family. J Interf Cytok Res 30(8):555–564

    Article  CAS  Google Scholar 

  • Du X, Williams DA (1997) Interleukin-11: review of molecular, cell biology, and clinical use. Blood 89:3897–3908

    CAS  PubMed  Google Scholar 

  • ExPASy. http://au.expasy.org/uniprot/Q9UBH0—(Expert Protein Analysis System) proteomics server of the Swiss Institute of Bioinformatics (SIB)

  • Fabbi M, Carbotti G, Ferrini S (2017) Dual roles of IL-27 in cancer biology and immunotherapy. Mediators Inflamm. Article ID 3958069, p 14. https://doi.org/10.1155/2017/3958069

    Article  Google Scholar 

  • Fort MM, Cheung J, Yen D et al (2001) IL-25 induces IL-4, IL-5, and IL-13 and Th2-associated pathologies in vivo. Immunity 15:985–995

    Article  CAS  Google Scholar 

  • Fry TJ, Mackall CL (2002) Interleukin-7: from bench to clinic. Blood 99:3892–3904

    Article  CAS  Google Scholar 

  • Garlanda C, Dinarello CA, Mantovani A (2013) Interleukin-1 family: back to the future. Immunity 39(6):1003–1018

    Article  CAS  Google Scholar 

  • Gilmour J, Lavender P (2008) Control of IL-4 expression in T-helper 1 and 2 cells. Immunology 124:437–444

    Article  CAS  Google Scholar 

  • Glue P, Fang JWS, Rouzier-Panis R et al (2000) Pegylated interferon-α2b: pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data. Clin Pharm Ther 68:556–567

    Article  CAS  Google Scholar 

  • Greenfeder S, Umland SP, Cuss FM et al (2001) Th2 cytokines and asthma: the role of interleukin-5 in allergic eosinophilic disease. Respir Res 2:71–79

    Article  CAS  Google Scholar 

  • HGNC. www.gene.ucl.ac.uk/nomenclature/—Gene families and grouping—Interferons (IFN)—Interleukins and interleukin receptor genes (IL)

  • Iwakura Y, Ishigame H, Saijo S, Nakae S (2011) Functional specialization of Interleukin-17 family members. Immunity 34:149–162

    Article  CAS  Google Scholar 

  • Kamimura D, Ishihara K, Hirano T (2003) IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physio Biochem Parmacol 149:1–38

    CAS  Google Scholar 

  • Kim S-H, Han S-Y, Azam T et al (2005) Interleukin 32: a cytokine and inducer of TNFα. Immunity 22:131–142

    CAS  PubMed  Google Scholar 

  • Klein C, Waldhauera I, Nicolinia VG et al (2017) Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. Oncoimmunology 6(3):15. https://doi.org/10.1080/2162402X.2016.1277306

    Article  CAS  Google Scholar 

  • Kotenko SV, Izotova LS, Mirochnitchenko OV et al (2001a) Identification of the functional IL-TIF (IL-22) receptor complex: the IL-10R2 chain (IL-10Rβ) is a common chain of both IL-10 and IL-TIF (IL-22) receptor complexes. J Biol Chem 276:2725–2732

    Article  CAS  Google Scholar 

  • Kotenko SV, Izotova LS, Mirochnitchenko OV et al (2001b) Identification, cloning and characterization of a novel soluble receptor which binds IL-22, and neutralizes its activity. J Immunol 166:7096–7103

    Article  CAS  Google Scholar 

  • Kristiansen OF, Mandrup-Paulsen T (2005) Interleukin-6 and diabetes: the good, the bad or the indifferent. Diabetes 54(Suppl 2):S114–S124

    Article  CAS  Google Scholar 

  • Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452

    Article  CAS  Google Scholar 

  • Liao W, Lin JX, Leonard WJ (2011) IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr Opin Immunol 23(5):598–604

    Article  CAS  Google Scholar 

  • Lieuw K (2017) Many factor VIII products available in the treatment of hemophilia A: an embarrassment of riches? J Blood Med 8:67–73

    Article  CAS  Google Scholar 

  • Lin H, Lee E, Hestir K et al (2008) Discovery of a cytokine and its receptor by functional screening of the extracellular proteome. Science 320(5877):807–811

    Article  CAS  Google Scholar 

  • Liu B, Nivick D, Kim SH, Rubinstein M (2000) Production of a biologically active human interleukin 18 requires its prior synthesis as PRO-IL-18. Cytokine 12(10):1519–1525

    Article  CAS  Google Scholar 

  • Ludwig CU, Ludwig-Habemann R, Obrist R et al (1990) Improved tolerance of interferon alpha-2a by continuous subcutaneous infusion. Onkologie 13:117–122

    CAS  PubMed  Google Scholar 

  • Lyman GH (2005) Pegfilgrastim: a granulocyte colony-stimulating factor with sustained duration of action. Expert Opin Biol Ther 5:1635–1646

    Article  CAS  Google Scholar 

  • Malek TR, Castro I (2010) Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33(2):153–165

    Article  CAS  Google Scholar 

  • Marrakchi S, Guigue P, Renshaw BL et al (2011) Interleukin-36–receptor antagonist deficiency and generalized Pustular psoriasis. N Engl J Med 365:620–628

    Article  CAS  Google Scholar 

  • Martinez-Moczygemba M, Huston DP (2003) Biology of common beta receptor-signalling cytokines: IL-3, IL-5 and GM-CSF. J Allergy Clin Immunol 112(4):653–665

    Article  CAS  Google Scholar 

  • Metcalf D (2008) Hematopoietic Cytokines. Blood 111(2):485–491

    Article  CAS  Google Scholar 

  • Ng EWM, Shima DT, Calias P et al (2006) Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease. Nat Rev 5:123–132

    CAS  Google Scholar 

  • Noelle RJ, Nowak EC (2010) Cellular source and immune functions of interleukin-9. Nat Rev 10:683–687

    Article  CAS  Google Scholar 

  • Nold MF, Nold-Petry CA, Zepp JA, Palmer BE, Bufler P, Dinarello CA (2010) IL-37 is a fundamental inhibitor of innate immunity. Nat Immunol 11:1014–1022

    Article  CAS  Google Scholar 

  • Pardo M, Castillo I, Oliva H et al (1997) A pilot study of recombinant interleukin-2 for treatment of chronic hepatitis C. Hepatology 26(5):1318–1321

    CAS  PubMed  Google Scholar 

  • Platanias L (2005) Mechanism of type I- and type II-interferon mediated signaling. Nat Rev Immunol 5:375–386

    Article  CAS  Google Scholar 

  • Pockros P, Patel K, O’Brien CB (2003) A multicenter study of recombinant human interleukin-12 for the treatment of chronic hepatitis C infection in patients with non-responsiveness to previous therapy. Hepatology 37:1368–1374

    Article  CAS  Google Scholar 

  • Reddy KR, Modi WM, Pedder S (2002) Use of peginterferon alfa-2a (40 KD) (Pegasys®) for the treatment of hepatitis C. Adv Drug Deliv Rev 54:571–586

    Article  Google Scholar 

  • Remick DG (2005) Interleukin-8. Crit Care Med 33(Suppl):S466–S467

    Article  Google Scholar 

  • Ross RJM, Leung KC, Maamra M et al (2001) Binding and functional studies with the growth hormone receptor antagonist, B2036-PEG (Pegvisomant), reveal effects of pegylation and evidence that it binds to a receptor dimer. J Clin Endocrinol Metab 86:1716–1723

    CAS  PubMed  Google Scholar 

  • Ryff JC (1996) Both cytokines and their antagonists have a place in clinical medicine. Eur Cytokine Netw 7:437. Abstract 40

    Google Scholar 

  • Schellekens H (2006) Erythropiesis-stimulating agents—present and future. European Endocrine Review Touch Briefings Publishers, Business Briefing

    Google Scholar 

  • Schmitz J, Owyang A, Oldham E et al (2005) IL-33, an Interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490

    Article  CAS  Google Scholar 

  • Setrerrahmane S, Xu H (2017) Tumor-related interleukins: old validated targets for new anti-cancer drug development. Mol Cancer 16:153–170

    Article  Google Scholar 

  • Steinman L (2007) A brief history of TH17, the first major revision in the TH1/TH2 hypothesis of T cell-mediated tissue damage. Nat Med 13(2):139–145

    Article  CAS  Google Scholar 

  • Towne JE, Garka KE, Renshaw BR, Virca GD, Sims JE (2004) Interleukin (IL)-F6m IL-1F8, and IL-1F9 signal through IL-Rrp2 and IL-1RacP to activate the pathway leading to NF-κB and MAPKs. J Biol Chem 279:13677–13688

    Article  CAS  Google Scholar 

  • Towne JE, Blair R, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, John E, Sims JE (2011) Interleukin-36 (IL-36) ligands require processing for full agonist (IL-36α, IL-36β and IL-36γ) or antagonist (IL-36Ra) activity. J Biol Chem 286:42594–42602

    Article  CAS  Google Scholar 

  • Trinchieri G (2003) Interleukin-12 and the regulation of innate resistance and adaptive immunity – review. Nat Rev Immunol 3:133–146

    Article  CAS  Google Scholar 

  • Trøseid M, Seljeflot I, Amesen H (2010) The role of interleukin-18 in the metabolic syndrome. Cardiovasc Diabetol 9:11–19

    Article  Google Scholar 

  • Tsai H-J, Jiang SS, Hung W-C et al (2017) A phase II study of arginine Deiminase (ADI-PEG20) in relapsed/refractory or poor-risk acute myeloid leukemia patients. Sci Rep 7:11253. https://doi.org/10.1038/s41598-017-10542-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Waldmann TA (2015) The shared and contrasting roles of interleukin-2 (IL-2) and interleukin in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. Cancer Immunol Res 3(3):219–227

    Article  CAS  Google Scholar 

  • Wang M, Liang P (2005) Interleukin-24 and its receptors. Immunology 114:166–170

    Article  CAS  Google Scholar 

  • Wang YS, Youngster S, Grace M, Bausch J, Bordens R, Wyss DF (2002) Structural and biological characterization of pegylated recombinant interferon alpha-2b and its therapeutic implications. Adv Drug Deliv Rev. 54(4):547–570

    Article  CAS  Google Scholar 

  • Wills RJ (1990) Clinical pharmacokinetics of interferons. Clin Pharmacokinet 19:390–399

    Article  CAS  Google Scholar 

  • Wills-Karp M (2004) Interleukin-13 in asthma pathogenesis. Immunol Rev 202:175–190

    Article  CAS  Google Scholar 

  • Xu W (2004) Interleukin-20. Int Immunopharmacol 4:527–633

    Article  Google Scholar 

  • Yi JS, Cox MA, Zajac AJ (2010) Interleukin-21: A multifunctional Regulator of Immunity to Infections. Microbes Infect 12(14–15):1111–1119

    Article  CAS  Google Scholar 

  • Yuan X, Peng X, Li Y and Li M (2015) Role of IL-38 and its related cytokines in inflammation. Mediators Inflamm. Article ID 807976, p 7. https://doi.org/10.1155/2015/807976

    Article  CAS  Google Scholar 

  • Zeuzem S, Hopf U, Carreño V et al (1999) A phase I/II study of recombinant human interleukin-12 in patients with chronic hepatitis C. Hepatology 29:1280–1286

    Article  CAS  Google Scholar 

  • Zeuzem S, Welsch C, Herrmann E (2003) Pharmacokinetics of Peginterferons. Semin Liver Dis 23(Suppl 1):23–28

    PubMed  Google Scholar 

Suggested Reading

    Interferons

    • Meager A (2006) The interferons: characterization and application. Wiley, Weinheim. ISBN:3-527-31180-7

      Google Scholar 

    • Pestka S, Krause CD, Walter M (2004a) Interferons, interferon-like cytokines, and their receptors. Immunol Rev 202:8–32

      Article  CAS  Google Scholar 

    • Pestka S (1981a) Interferons. In: Pestka S (ed) Methods in enzymology, vol 78. Academic, New York, p 632

      Google Scholar 

    • Pestka S (1981b) Interferons. In: Pestka S (ed) Methods in enzymology, vol 79. Academic, New York, p 677

      Google Scholar 

    • Pestka S (1986) Interferons. In: Pestka S (ed) Methods in enzymology, vol 119. Academic, New York, p 845

      Google Scholar 

    • Special Issue (2005) The neoclassical pathways of interferon signaling. J Interferon Cytokine Res 25:731–811

      Google Scholar 

    Interleukins

    • Pestka S, Krause CD, Sarkar C (2004b) IL-10 and related cytokines and receptors. Ann Rev Immunol 22:929–979

      Article  CAS  Google Scholar 

    • Sigal LH (2004) Interleukins of current clinical relevance (part I). J Clin Rheumatol 10:353–359

      Article  Google Scholar 

    • Sigal LH (2004) Interleukins of current clinical relevance (part II). J Clin Rheumatol 11:34–39

      Article  Google Scholar 

    PEGylation

    • Bailon P, Palleroni A, Schaffer CA et al (2001) Rational design of a potent, long-lasting form of interferon: a 40 kDa branched polyethylene glycole conjugated interferon α-2a for the treatment of hepatitis C. Bioconjugate Chem 12:195–202

      Article  CAS  Google Scholar 

    • Roberts MJ, Bentley MD, Harris JM (2002) Chemistry for peptide and protein PEGylation. Adv Drug Deliv Rev 54:459–476

      Article  CAS  Google Scholar 

    Download references

    Author information

    Authors and Affiliations

    Authors

    Editor information

    Editors and Affiliations

    Rights and permissions

    Reprints and permissions

    Copyright information

    © 2019 Springer Nature Switzerland AG

    About this chapter

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this chapter

    Ryff, JC., Pestka, S. (2019). Interferons and Interleukins. In: Crommelin, D., Sindelar, R., Meibohm, B. (eds) Pharmaceutical Biotechnology. Springer, Cham. https://doi.org/10.1007/978-3-030-00710-2_27

    Download citation

    Publish with us

    Policies and ethics