Interleukin‐4

Abstract

IL‐4 is a pleiotropic cytokine and has broad effects on a variety of cells, tissues, organs and their biological activities. It is also a well‐known ‘regulatory’ cytokine to the immune system produced mainly by activated Th2 cells and some other cells. Despite its influences on different organs and metabolic activities, IL‐4 possesses important roles in the immune system and immune responses. Understanding of these specific features of IL‐4 will help the design and development of potential therapeutic strategies against many diseases, including allergy, autoimmune and infectious diseases.

Key Concepts

  • Interleukin‐4 is a pleiotropic cytokine involved in a variety of bio‐physiological activities.
  • Interleukin‐4 is considered as a regulatory cytokine and contributes to the treatment of autoimmune diseases by shifting the Th1/Th2 paradigm as well as inducing other modulatory mechanisms.
  • The time and the amount, as well as the producers and responders of interleukine‐4, determine its effects on the immune reactions.
  • An excessive amount of interleukin‐4 deteriorates Treg‐mediated immune suppression through the enhancement of responder T‐cell survival.
  • The presence of interleukin‐4 at a physiological relevant concentration is beneficial to the suppressive immune responses elicited by regulatory T‐cells.

Keywords: interleukin‐4; Th1/Th2 balance; regulatory cytokine; regulatory T‐cells; autoimmune disease

Figure 1. Pleiotropic effects of IL‐4 on physiological and immunological activities. This figure illustrates the important physiological and immunological features of IL‐4. With the wide expression of IL‐4 receptors, IL‐4 acts widely and differentially on various cells, tissues and organs. In the physiological aspect, IL‐4 supports the integral functions including memory, learning and spatial recognition of the brain. IL‐4 also stimulates the proper growth of muscle cells and activates hepatocytes for liver regeneration. IL‐4 involves in the regulation of lipid metabolism and enhancement of insulin action. In addition to its role in supporting B cell proliferation and class switching, IL‐4 serves as the critical factor for the differentiation Th2 lineage as well as M2 macrophages. Interestingly, IL‐4 takes participate in Treg‐mediated immune suppression in a concentration‐dependent manner. High concentration of IL‐4 endows effector T cells (Teffs) with antiapoptotic activities which in turn counteracts the suppressive mechanisms utilized by Tregs whereas physiological relevant concentration of IL‐4 supports such reactions partly by preservation of the survival and granzyme production in Tregs. Some motifolio templates were utilised for illustration.
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References

Aronica MA, Goenka S and Boothby M (2000) IL‐4‐dependent induction of BCL‐2 and BCL‐XL in activated T lymphocytes through a STAT6‐ and PI3‐kinase‐independent pathway. Cytokine 12: 578–587.

Beal AM, Ramos‐Hernandez N, Riling CR, Nowelsky EA and Oliver PM (2012) TGF‐beta induces the expression of the adaptor Ndfip1 to silence IL‐4 production during iTreg cell differentiation. Nature Immunology 13: 77–85.

Cameron MJ, Arreaza GA, Zucker P, et al. (1997) IL‐4 prevents insulitis and insulin‐dependent diabetes mellitus in nonobese diabetic mice by potentiation of regulatory T helper‐2 cell function. Journal of Immunology 159: 4686–4692.

Dardalhon V, Awasthi A, Kwon H, et al. (2008) IL‐4 inhibits TGF‐beta‐induced Foxp3+ T cells and, together with TGF‐beta, generates IL‐9+ IL‐10+ Foxp3− effector T cells. Nature Immunology 9: 1347–1355.

Domingues HS, Mues M, Lassmann H, Wekerle H and Krishnamoorthy G (2010) Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS ONE 5: e15531.

Dorsey NJ, Chapoval SP, Smith EP, et al. (2013) STAT6 controls the number of regulatory T cells in vivo, thereby regulating allergic lung inflammation. Journal of Immunology 191: 1517–1528.

Erb KJ, Ruger B, von Brevern M, et al. (1997) Constitutive expression of interleukin (IL)‐4 in vivo causes autoimmune‐type disorders in mice. Journal of Experimental Medicine 185: 329–339.

Falcone M, Yeung B, Tucker L, et al. (2001) IL‐4 triggers autoimmune diabetes by increasing self‐antigen presentation within the pancreatic Islets. Clinical Immunology 98: 190–199.

Gadani SP, Cronk JC, Norris GT and Kipnis J (2012) IL‐4 in the brain: a cytokine to remember. Journal of Immunology 189: 4213–4219.

Ghoreschi K, Thomas P, Breit S, et al. (2003) Interleukin‐4 therapy of psoriasis induces Th2 responses and improves human autoimmune disease. Nature Medicine 9: 40–46.

Goh YP, Henderson NC, Heredia JE, et al. (2013) Eosinophils secrete IL‐4 to facilitate liver regeneration. Proceedings of the National Academy of Sciences of the United States of America 110: 9914–9919.

Horsley V, Jansen KM, Mills ST and Pavlath GK (2003) IL‐4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell 113: 483–494.

Howard M, Farrar J, Hilfiker M, et al. (1982) Identification of a T cell‐derived b cell growth factor distinct from interleukin 2. Journal of Experimental Medicine 155: 914–923.

Khoury SJ, Hancock WW and Weiner HL (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. Journal of Experimental Medicine 176: 1355–1364.

Lafaille JJ, Keere FV, Hsu AL, et al. (1997) Myelin basic protein‐specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease. Journal of Experimental Medicine 186: 307–312.

Pace L, Pioli C and Doria G (2005) IL‐4 modulation of CD4+CD25+ T regulatory cell‐mediated suppression. Journal of Immunology 174: 7645–7653.

Pace L, Rizzo S, Palombi C, Brombacher F and Doria G (2006) Cutting edge: IL‐4‐induced protection of CD4+CD25− Th cells from CD4+CD25+ regulatory T cell‐mediated suppression. Journal of Immunology 176: 3900–3904.

Pakala SV, Kurrer MO and Katz JD (1997) T helper 2 (Th2) T cells induce acute pancreatitis and diabetes in immune‐compromised nonobese diabetic (NOD) mice. Journal of Experimental Medicine 186: 299–306.

Pandiyan P and Lenardo MJ (2008) The control of CD4+CD25+Foxp3+ regulatory T cell survival. Biology Direct 3: 6.

Paul WE (2015) History of interleukin‐4. Cytokine 75: 3–7.

Pillemer BB, Qi Z, Melgert B, et al. (2009) STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells. Journal of Immunology 183: 155–163.

Prochazkova J, Fric J, Pokorna K, et al. (2009) Distinct regulatory roles of transforming growth factor‐beta and interleukin‐4 in the development and maintenance of natural and induced CD4+ CD25+ Foxp3+ regulatory T cells. Immunology 128: e670–e678.

Ricardo‐Gonzalez RR, Red Eagle A, Odegaard JI, et al. (2010) IL‐4/STAT6 immune axis regulates peripheral nutrient metabolism and insulin sensitivity. Proceedings of the National Academy of Sciences of the United States of America 107: 22617–22622.

Sanchez‐Guajardo V, Tanchot C, O'Malley JT, et al. (2007) Agonist‐driven development of CD4+CD25+Foxp3+ regulatory T cells requires a second signal mediated by Stat6. Journal of Immunology 178: 7550–7556.

Shaw MK, Lorens JB, Dhawan A, et al. (1997) Local delivery of interleukin 4 by retrovirus‐transduced T lymphocytes ameliorates experimental autoimmune encephalomyelitis. Journal of Experimental Medicine 185: 1711–1714.

Shen CR, Mazza G, Perry FE, et al. (1996) T‐helper 1 dominated responses to erythrocyte Band 3 in NZB mice. Immunology 89: 195–199.

Shen CR, Youssef AR, Devine A, et al. (2003) Peptides containing a dominant T‐cell epitope from red cell Band 3 have in vivo immunomodulatory properties in NZB mice with autoimmune hemolytic anemia. Blood 102: 3800–3806.

Skapenko A, Kalden JR, Lipsky PE and Schulze‐Koops H (2005) The IL‐4 receptor alpha‐chain‐binding cytokines, IL‐4 and IL‐13, induce forkhead box P3‐expressing CD25+CD4+ regulatory T cells from CD25−CD4+ precursors. Journal of Immunology 175: 6107–6116.

Thornton AM, Piccirillo CA and Shevach EM (2004) Activation requirements for the induction of CD4+CD25+ T cell suppressor function. European Journal of Immunology 34: 366–376.

Tian J, Atkinson MA, Clare‐Salzler M, et al. (1996) Nasal administration of glutamate decarboxylase (GAD65) peptides induces Th2 responses and prevents murine insulin‐dependent diabetes. Journal of Experimental Medicine 183: 1561–1567.

Trembleau S, Penna G, Bosi E, et al. (1995) Interleukin 12 administration induces T helper type 1 cells and accelerates autoimmune diabetes in NOD mice. Journal of Experimental Medicine 181: 817–821.

Tsao CH, Shiau MY, Chuang PH, Chang YH and Hwang J (2014) Interleukin‐4 regulates lipid metabolism by inhibiting adipogenesis and promoting lipolysis. Journal of Lipid Research 55: 385–397.

Vella AT, Dow S, Potter TA, Kappler J and Marrack P (1998) Cytokine‐induced survival of activated T cells in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 95: 3810–3815.

Venmar KT, Kimmel DW, Cliffel DE and Fingleton B (2015) IL4 receptor alpha mediates enhanced glucose and glutamine metabolism to support breast cancer growth. Biochimica et Biophysica Acta 1853: 1219–1228.

Verma ND, Plain KM, Nomura M, et al. (2009) CD4+CD25+ T cells alloactivated ex vivo by IL‐2 or IL‐4 become potent alloantigen‐specific inhibitors of rejection with different phenotypes, suggesting separate pathways of activation by Th1 and Th2 responses. Blood 113: 479–487.

Vignali DA, Collison LW and Workman CJ (2008) How regulatory T cells work. Nature Reviews. Immunology 8: 523–532.

Wang Y, Su MA and Wan YY (2011) An essential role of the transcription factor GATA‐3 for the function of regulatory T cells. Immunity 35: 337–348.

Wei J, Duramad O, Perng OA, et al. (2007) Antagonistic nature of T helper 1/2 developmental programs in opposing peripheral induction of Foxp3+ regulatory T cells. Proceedings of the National Academy of Sciences of the United States of America 104: 18169–18174.

Wurster AL, Withers DJ, Uchida T, White MF and Grusby MJ (2002) Stat6 and IRS‐2 cooperate in interleukin 4 (IL‐4)‐induced proliferation and differentiation but are dispensable for IL‐4‐dependent rescue from apoptosis. Molecular and Cellular Biology 22: 117–126.

Yang WC, Hwang YS, Chen YY, et al. (2017) Interleukin‐4 supports the suppressive immune responses elicited by regulatory T cells. Frontiers in Immunology 8: 1508.

Youssef AR, Shen CR, Lin CL, Barker RN and Elson CJ (2005) IL‐4 and IL‐10 modulate autoimmune haemolytic anaemia in NZB mice. Clinical and Experimental Immunology 139: 84–89.

Zamorano J, Mora AL, Boothby M and Keegan AD (2001) NF‐kappa B activation plays an important role in the IL‐4‐induced protection from apoptosis. International Immunology 13: 1479–1487.

Further Reading

Bao K and Reinhardt RL (2015) The differential expression of IL‐4 and IL‐13 and its impact on type‐2 immunity. Cytokine 75: 25–37.

Colonna M (2018) Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48: 1104–1117.

Junttila IS (2018) Tuning the cytokine responses: an update on interleukin (IL)‐4 and IL‐13 receptor complexes. Frontiers in Immunology 9: 888.

Shea‐Donohue T, Sun R, Bohl JA, McLean LP and Zhao A (2015) Enteric nematodes and the path to up‐regulation of type 2 cytokines IL‐4 and IL‐13. Cytokine 75: 62–67.

Van Dyken SJ and Locksley RM (2013) Interleukin‐4‐ and interleukin‐13‐mediated alternatively activated macrophages: roles in homeostasis and disease. Annual Review of Immunology 31: 317–343.

Wang X, Lupardus P, Laporte SL and Garcia KC (2009) Structural biology of shared cytokine receptors. Annual Review of Immunology 27: 29–60.

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Yang, Wei‐Cheng, Hwang, Yih‐Shiou, and Shen, Chia‐Rui(Nov 2018) Interleukin‐4. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0028195]