Interleukins in Therapeutics!
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May
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ragupathyrenganathan
Interleukins in Therapeutics!
Formulation Discussion
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ABOUT AUTHOR:
Anjan Khadka
Department of Pharmacology,
AFMC, Pune, India
anjankhadka14@yahoo.com

ABSTRACT:
Interleukins are a subset of a larger group of cellular messenger molecules called cytokines, which are modulators of cellular behaviour. On the basis of their respective cytokine profiles, responses to chemokines, and interactions with other cells, these T-cell subsets can promote different types of inflammatory responses. During the development of allergic disease, effector TH2 cells produce IL-4, IL-5, IL-9, and IL-32.  IL-25, IL- 31, and IL-33 contributes to TH2 responses and inflammation. These cytokines have roles in production of allergen-specific IgE, eosinophilia, and mucus. ILs have role in therapeutics as well as diagnosis and prognosis as biomarker in various conditions. Therapeutic targeting of the IL considered to be rational treatment strategy and promising biologic therapy.

INTRODUCTION:
Interleukinsare group of cytokines that were first seen to be expressed by leucocytes and they interact between cells of the immune systems. It is termed by Dr. Vern Paetkau (University of Victoria) in 1979. Interleukins (IL) are able to promote cell growth, differentiation, and functional activation. The question of how diverse cell types communicate with each other hadled to the discovery of interleukins. The name interleukin was chosen because it reflected the basic property of these mediators to serve as communication links between leukocytes.1,2 Effects of ILs has greatly increased since the discoveries of monocyte IL (called IL-1) and lymphocyte IL (called IL-2); more than 40 cytokines are now designated as ILs.3

Cytokines are low molecular weight regulatory proteins or glycoproteins secreted by white blood cells & other cells in the body in response to various stimuli.Cytokine is a word that comes from cyto meaning “cell” and kinin meaning ‘hormones’. It was Stanley Cohen in 1974 who for the first time introduced the term ‘‘cytokine’’. It includes lymphokines, monokines, interleukins, and colony stimulating factors (CSFs), interferons (IFNs), tumor necrosis factor (TNF) and chemokines. The majority of interleukins are synthesized by helper CD4 T lymphocytes, as well as through monocytes, macrophages, and endothelial cells. They promote the development and differentiation of T, B, and hematopoietic cells.1,2,3

Properties of cytokines: Based on function1,3

  1. Hormone like action: autocrine, paracrine, endocrine
  2. One cytokine can affect more than one types of cells – Pleiotropism
  3. Different cytokines can perform some similar functions – Redundancy
  4. One cytokine can influence the function(s) and/or production of other cytokines- Multifunctional

Classification of Cytokines:Based on principal action2,3

Principal action

Mediators of innate immunity

Mediators of specific immunity

Stimulate growth of BM progenitors

Source

Mononuclear phagocytes

Ag stimulated T lymphocytes

BM cells, T cells

Cytokines

IL1

IL6

IL10

IL12

IL15

Type I IFN

Chemokines

IL2

IL4

IL5

TGF ß

IFN α

TNF

IL3

IL7

GM-CSF

M-CSF

G-CSF

Classification of interleukins: Based on shared structural characteristics, and/or shared receptor subunits and/or shared chromosomal locations2,3,4,5

Family

Interleukins

Functions

IL-1 family

IL-1α, IL-1β, IL-18 , IL-33

Co-stimulation of T helper cells; Maturationand proliferation of B cells; Activation of NK cells; Role in inflammation acute phase reactions and fever.

IL-2 family

IL-2, IL-4,  IL-7, IL-9,  IL-13, IL-15, IL-21

Stimulates growth and differentiation of  cell response; IgG and IgE synthesis (important in allergic response);

Used as Immunotherapy to treat cancer or suppressed for transplant patients; Used in clinical trials to raise CD4 counts in HIV positive patients

IL-10 family

IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, IL-29

Cytokine production; Histamine release; Inhibits Th1 cytokine production (IFN gamma, TNF-beta, IL-2); Osteoclast formation

IL-12 family

IL-12, IL-23, IL-27

Differentiation into cytotoxic T cells with IL-2; Increase IFN-gamma and TNF-alpha, Decrease IL-10; iincrease TNF-alpha and  IFN-gamma

IL-17 family

IL-17A–F, IL-25

Angiogenesis; Increase inflammatory cytokines; Pro inflammatory role in asthma;  Induces production of IL-4, IL-5 and IL-13, which stimulate eosinophil expansion

Family of ‘Like’ cytokines

IL-3, IL-5 ,IL-6 and IL-11

Differentiation of activated B cells into plasma cell; Antibody secretion; Osteoclast formation; Acute phase reaction, hematopoiesis, differentiation, inflammation, etc.

Fig: Interleukin-6 as multifunctional interleukins3,8

Fig: Cytokine cascade links inflammatory and immune responses3,8,9

ROLE OF INTERLEUKINS AND THEIR INHIBITORS IN THERAPEUTICS:

Aldesleukin is proleukin, a lymphokine, human recombinant interleukin-2. It stimulates the growth of IL-2 dependent cells, triggers natural killer (NK) and lymphokine-activated killer (LAK) cell activity. It Induces production of interferon gamma, and increases lymphocyte cytotoxicity. It is used for treatment of adults with metastatic renal cell carcinoma, melanoma and bone tumour.3,10,11,12

Interleukin Inhibitors

1.    TNF-alpha inhibitors:Etanercept, Infliximab, Adalimumab

2.    IL-1 receptor antagonist:Anakinra, Rilonacept, Canakinumab, Endogenous IL1RA

3.    IL-2 receptor antagonist (Anti CD25):Daclizumab, Basiliximab

4.    IL-4 antagonist:Pascolizumab

5.    IL-4 and IL-13 antagonist:   Pitrakinra

6.    Anti IL-5:Mepolizumab

7.    Anti IL-6: Ruxolitinib, Tocilizumab, Bevacizumab, Cucurbitacin, Siltuximab

8.    IL-13 inhibitors: Tralokinumab, Lebrikizumab

9.    IL-17 inhibitors: Vidofludimus, Ustekinumab

Anakinra is a recombinant, IL-1 receptor antagonist. It is used as single daily subcutaneous injection at recommended fixed daily dose of 100 mg.it has been approved for use in rheumatoid arthritis and neonatal onset multisystem inflammatory disease. Neutrophil counts prior and while receiving anakinra, monthly for 3 months, and thereafter quarterly for a period up to 1 year is required.3,12,13

Daclizumab is a therapeutic humanized monoclonal antibody to IL-2R. It is used to prevent rejection in organ transplantation, especially in kidney transplants. Its recommended dose is 1.0 mg/kg and given in multiple doses, the first 1 hour before the transplant operation and 5 further doses given at two week intervals after the transplant. Phase II clinical trial hasbeen completed for its possible use in Multiple Sclerosis.3,8,14

Basiliximab is chimeric mouse-human monoclonal antibody IL-2R. It is used to prevent rejection in organ transplantation, especially in kidney transplants. Its dose is 20 mg two times 4 days apart -given in two doses, the first within 2 hours of the start of transplant operation and the second 4 days after the transplant. Lichen planus have been successfully treated with basiliximab as an alternative therapy to cyclosporine, with a dose of 20 mg every 4 days.3,6,8,15

Tocilizumab is a humanized anti-interleukin-6 receptor antibody of IgG 1 class. It has been used invarious conditions like autoimmune diseases (SLE, RA, Systemic sclerosis, Polymyositis , Takayasu arteritis and giant cell arteritis, Crohns’ disease), chronic inflammatory conditions (Castleman’s disease, Systemic juvenile idiopathic arthritis and adult onset still’s disease, Amyloid A Amyloidosis, Bechet syndrome) and malignant diseases (Gliobastoma multiforme, renal cell carcinoma, prostate cancer, mesothelioma, multiple myeloma).3,10,17,19

Newer Interleukin inhibitors
· Pitrakinra is a IL-4 and IL-13 antagonist in phase IIa studies for asthma

· Mepolizumab is a humanized monoclonal antibody that recognizes IL-5 and used to treat asthma, white blood cell diseases and hypereosinophilic syndrome.

· Tralokinumabis a human monoclonal antibody which targets interleukin 13 and is designed for treatment of asthma. Phase II trial is undergoing to evaluate in patients with active, moderate-to-severe ulcerative colitis.

· Lebrikizumab is a humanized monoclonal antibody and used as experimental immunosuppressive drug for the treatment of asthma that cannot be adequately controlled with inhalable glucocorticoids (successful Phase II clinical trial).3,10

Miscellaneous agents

  • Cyclosporin inhibits IL-1 and IL-2 receptor production.
  • Auranofininhibits release of IL-1 and TNF-alpha.
  • Raloxifeneinhibits IL-6 production by human trabecular osteoblast.
  • Clarithromycininhibits IL-13 induced goblet cell hyperplasia in human airway cells.
  • Methylprednisolone inhibits IL-8 and IL-6 during open heart surgery.
  • Simvastatininhibits IL-6 release in human monocytes stimulated by C-reactive protein and lipopolysaccharide.
  • Testosterone inhibits IL-6 production of normal and gingival fibromatosis.

Interleukins in pregnancy
TNF-α has a characteristic inflammatory action, and it is an additional diabetogenic factor in pregnancy. The loss of the control of the production of these cytokines, with increase of TNF-α, is related to the risk for developing obstetric complications, particularly recurrent fetal loss, GDM, hypertensive syndromes, and fetal growth restriction. IL-10 is an important cytokine for pregnancy maintenance and development. During this specific period, its immunosuppressive action plays a key role in regulating the balance of pro- and anti-inflammatory signs that orchestrate the adequate development of pregnancy and in placental growth and remodeling, which are also important for a favorable pregnancy outcome.3,13,14,15

Interleukins as bio-markers
IL-6 provides a promising serum marker for the nonsurgical prediction of endometriosis. IL-8 is a promising marker for many clinical conditions such as chronic prostatitis, acute pyelonephritis, non-Hodgkin’s lymphoma, urinary bladder cancer, therapeutic target to control cancer growth and metastasis, nosocomial bacterial infections in neonatal intensive care unit (NICU), vesicoureteral reflux (VUR), Detection of pulmonary infections and osteomyelitis. BothIL-6 and IL-8 are used as marker for acute pyelonephritis, early biomarker of acute kidney injury andpredict prolonged mechanical ventilation. Il-13 is used as biomarker for asthma.3,10,16,17,18

Recent advances in interleukins
IL-2 acts as novel targets for several autoimmune diseaseIL-1B converting enzyme inhibitors decreases death rate in severe acute experimental pancreatitis- promising future studies. IL-1R antagonist appear as new therapy in type 2 diabetes mellitus. DIRA-Deficiency of IL-1 receptor antagonist is a new autoimmune disease related to skin disruption manifests in first 3 weeks of life as fetal distress, joint swelling, oral mucosal lesions and painful movement. Interleukin-10 may protect against progressing injury during the acute phase of ischemic stroke.3,6,7,9,17,19,20

CONCLUSION
IL contributes to host defense against pathogens. Dysregulation of IL production plays a significant pathological role in various autoimmune, inflammatory diseases and malignancy. Therapeutic targeting of the IL considered to be rational treatment strategy and promising biologic therapy. Research is continuing with an aim to develop new therapies and refine those already in use.

References
1.Vandana T, Bhupinder S K: Cytokines and anti-cytokines as therapeutics — An update.European Journal of Pharmacology 579 (2008) 1–12
2.Toshio T, Masashi N, Tadamitsu K: Therapeutic Targeting of the Interleukin-6 Receptor. Annu Rev Pharmacol Toxicol. 2012. 52:199–219
3.M€ubeccel Akdis, Simone Burgler,Reto Crameri, Thomas Eiwegger,Hiroyuki Fujita, Enrique Gomez et al.:Interleukins, from 1 to 37, and interferon-g: Receptors,functions, and roles in diseases.Allergy Clin Immunol,2011.127,702-721(e1-45)
4.Gabriele G, David B, Joan R: Interleukin 13 and the evolution of asthma therapy. Am J Clin Exp Immunol 2012;1(1):20-27
5.Aamir Shahzad, Martin Knapp, Irene Lang, Gottfried Köhler: Interleukin 8 (IL-8) – a universal biomarker?International Archives of Medicine 2010, 3:11
6.Jusciele B , AnaMaria CR, Joice MV:Interleukin 10 and Tumour Necrosis Factor-Alpha in Pregnancy:Aspects of Interest in Clinical Obstetrics. ISRN Obstetrics and Gynecology Volume 2012.
7.Lippincott’s Illustrated Reviews: Immunology.Paperback.Publisher: Lippincott Williams & Wilkins; (July 1, 2007)
8.Sadaf Ejaz: Role of inflammatory cytokines in inflammation and cancer. Journal of Public Health and Biological Sciences Vol. 2, No. 1 Jan – Mar 2013, p.173-182
9.Brint EK, Xu D, Liu H: ST2 is an inhibitor of interleukin 1 receptor and toll-like receptor 4 signaling and maintains endotoxin tolerance. Nat Immunol 2004; 5:373–9.
10.Miller AM, Xu D, Asquith DL: IL-33 reduces the development of atherosclerosis. J Exp Med 2008; 205:339–46.
11.P. Kidd: Th1/Th2 balance: the hypothesis, its limitations, and implications for health and disease. Alternative Medicine Review, 2003, 8, 223–46
12.S. Hauguel-de Mouzon, M. Guerre-Millo: The placenta cytokine network and inflammatory signals,Placenta, 2006, 27,794–98.
13.Dmowski WP, Lesniewicz R, Rana N, Pepping P, Noursalehi M: Changing trends in the diagnosis of endometriosis: a comparative study of women with pelvic endometriosis presenting with chronic pelvic pain or infertility. Fertil Steril 1997; 67:238–43.
14.Jamilloux Y, Henry T: The inflammasomes: platforms of innate immunity. Med Sci (Paris). 2013; 29:975-84.
15.Sparmann A, Bar-Sagi D: Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell 2004; 6(1): 447–58.
16.Schmitz J, Owyang A, Oldham: 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 2005; 23: 479–90.
17.Wong JY, De Vivo I, Lin X, Fang SC, Christiani DC: The Relationship between Inflammatory Biomarkers and Telomere Length in an Occupational Prospective Cohort Study. PLoS One. 2014 Jan 27; 9(1):e87348.
18.Tang XQ, Sun WP, Xu HB, Liu WB, Wang TS, Liu HJ:The changes in the levels of IL-6, IL-17, and IL-21 in the acute stage of childhood asthma.Clin Lab. 2013; 59(11-12):1381-7.
19.McLean MH, Neurath MF, Durum SK: Targeting Interleukins for the Treatment of Inflammatory Bowel Disease-What Lies Beyond Anti-TNF Therapy? Inflamm Bowel Dis. 2014; 20(2):389-97.
20.Fedorkiv MB, Hudz IM, Shevchuk IM: Prognostication of acute-pancreatitis-associated pulmonary injury based on determination of cytokines levels. Klin Khir. 2013 Jul;(7):28-30



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