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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 2  |  Page : 70-75

Interleukins in Periodontics


1 Department of Periodontics, Rural Dental College, Pravara Institute of Medical Sciences, Ahmednagar, Maharashtra, India
2 Department of OMFS, Rural Dental College, Pravara Institute of Medical Sciences, Ahmednagar, Maharashtra, India
3 Department of Prosthodontics, Rural Dental College, Pravara Institute of Medical Sciences, Ahmednagar, Maharashtra, India

Date of Submission03-Jul-2020
Date of Decision07-Jul-2020
Date of Acceptance15-Aug-2020
Date of Web Publication8-Dec-2020

Correspondence Address:
Shivani Sachdeva
Department of Periodontics, Rural Dental College, Pravara Institute of Medical Sciences, Loni, Ahmednagar, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jhnps.jhnps_26_20

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  Abstract 


Key modulators of inflammation are interleukins (ILs). There is a complex network of interactions in acute and chronic inflammation which is modulated by ILs. Mechanistic explanations for positive and negative interactions between individual ILs will also depend on new insights into the signal transduction pathways for each IL. ILs are the cytokines that act specifically as mediators between leukocytes. Approximately more than 35 ILs have been described, each having unique biological activity and role in periodontal health or disease. It seems quite likely that the lymphocyte may behave in a manner similar as a neuron that receives information from several other neurons and integrates the positive and negative signals and then corresponds accordingly by initiating or refraining from initiating action potential. Like a neuron, the response of the lymphocyte will depend both on the positive and negative signals and also on the nature of their individual signal transduction pathways.

Keywords: Bone resorption, cytokines, interleukins in periodontics, osteoblastic activity


How to cite this article:
Sachdeva S, Saluja H, Mani A, Sonkar T. Interleukins in Periodontics. J Head Neck Physicians Surg 2020;8:70-5

How to cite this URL:
Sachdeva S, Saluja H, Mani A, Sonkar T. Interleukins in Periodontics. J Head Neck Physicians Surg [serial online] 2020 [cited 2021 Apr 18];8:70-5. Available from: https://www.jhnps.org/text.asp?2020/8/2/70/302623




  Introduction Top


The response of tissue to injury is inflammation, which is characterized in the acute phase by increase in the flow of blood and permeability. There is an accumulation of leukocyte, fluid, and inflammatory mediators better known as cytokines. In the subacute and chronic phase, we see the development of specific humoral and cellular immune responses. During acute as well as chronic inflammatory processes, a variety of soluble factors are involved.[1]

There is a large diversity of soluble factors which includes a group of secreted polypeptides known as cytokines.[2] These cytokines are inflammatory and can be present in two groups:

  1. Acute inflammation
  2. Chronic inflammation



  Cytokines Top


Cytokines (Greek cyto-, cell; and -kinos, movement) are a category of signaling molecules that, like hormones and neurotransmitters, are used extensively in cellular communication. They are proteins, peptides, or glycoproteins.[3],[4],[5],[6]

Often secreted by immune cells, they encounter a pathogen, thereby activating and recruiting immune cells further to increase the system’s response toward the pathogen. Cytokines are key modulators of inflammation. [Figure 1] depicts various cytokines involved in inflammation.
Figure 1: Cytokines involved in acute and chronic inflammatory responses

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  Interleukins Top


The interaction between immune and inflammatory cells is mediated in large part by proteins, termed interleukins (ILs) which promote cell growth differentiation, and functional activations. Approximately more than 35 ILs have been described, each having unique biological activity.

ILs are a group of cytokines (secreted signaling molecules) that were first seen to be expressed by white blood cells (leukocytes) as a means of communication (inter-). The term was coined by Dr. Vern Paetkau (1979) from University of Victoria; it has since been found that ILs are produced by a wide variety of body cells.


  Various Interleukins and Periodontal Implications Top


Interleukin-1

IL-1 was originally classified as a product of activated macrophages; it may be produced by other cell types including fibroblasts, endothelial cells, keratinocytes, and smooth muscle cells, which will, in turn, mediate the inflammatory response of the host. The two prime forms in innate immunity are designated a form and b form. Both the forms have indistinguishable biological activity.

IL 1 can regulate various aspects of T cell and B cell lymphocytic development and functional activation, including the maturation of thymic T cells and B cell precursors. It also regulates the induction, synthesis, it’s expression and lymphocyte proliferation.[3]

IL-1 can also function as a pyrogen, inducing significant elevations in body temperature.

Synonyms

  • B-cell activating factor
  • Catabolin
  • Endogenous pyrogen.


General characteristics

The IL-1 family has three members as IL-1 α, IL-1 β, and IL-1 receptor antagonist. All three act on the same receptor.

Periodontal implications

Interleukin-1α

Various studies to measure the amount of IL 1α levels present in gingival crevicular fluid (GCF) in both diseased as well as on the healthy sites have been conducted. It has been implicated as being the active entity involved in bone resorption. Furthermore, it also has an auto-stimulatory effect, i.e., it is amplified and perpetuated on its own production.[4]

Certain studies have mentioned the possibility of IL-1α in playing a modulating role in the process of bone resorption in combination with epidermal growth factor.

Interleukin-1 β

It is a predominant form of IL-1 found in the periodontal tissues, which is primarily produced by macrophages. It is important in periodontal tissues due to its potency in inhibiting formation of bone and enhancing bone resorption.

It plays a pivotal role in the inflammatory cascade in response to bacterial lipopolysaccaride. Numerous studies have shown that levels of IL-1 β are increased in GCF collected from diseased periodontal sites. Since it can stimulate prostaglandin synthesis and enhance protease production in many cell types including fibroblast and osteoblast, it is believed to induce many pro-inflammatory or catabolic effects which may contribute in the destruction of bone and surrounding connective tissue of teeth in periodontitis. IL-1 β has also been suggested to be a major link in the development of phenytoin-induced gingival overgrowth. Some studies reported that IL-1 β may also control local levels of IL-8.[5]

Gamonal J. et al. (2000) reported findings of IL 1 β in 94% sites of patients suffering from periodontitis, with a mean level of 64 pg. IL 1 β was not detectable in the healthy sites and its levels in diseased sites decreased appreciably 2 months after periodontal treatment.[5]

There is an evident role of IL-1 in causing bone loss, which is stimulated by periodontal pathogens. This has been evident after studying human and animal models. In human models, the levels of IL-1 β were elevated in GCF at sites of the latest bone and clinical attachment loss in periodontal patients.[7],[8]

IL-1 β is a potent stimulator of bone resorption and has been implicated in the pathogenesis of periodontal destruction.

Interleukin-2

It is secreted by T-lymphocytic cell which acts to regulate the immune response. Biochemical studies revealed that IL-2 is a glycoprotein.

Synonym

  • T-cell growth factor.


Periodontal implications

IL-2 synthesis has recently been associated with destructive processes such as rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Whether IL-2 directly stimulates bone resorption is still controversial, but it may have the potential to destroy bone indirectly through stimulation of other cell types.

Interleukin-3

It is a T-lymphocyte-derived glycoprotein that ropes the viability and differentiation of lymphoid and hematopoietic stem cells.

Synonyms

  • Hemopoietic growth and differentiation factor
  • Burst promoting factor
  • P-cell-stimulating factor
  • Mast cell growth factor
  • Multi-colony-stimulating factor.


Clinical significance

It plays an important role in chronic allergic diseases.

Interleukin-4

The activation of this lymphokine is done by T-cells. IgE immune reactions and eosinophil-mediated responses are its principal role. It also stimulates B-cells for its production of IgE. IL 4 is a growth and differentiation factor which expresses Th 2 cells. It further activates the production of few adhesion molecules on endothelial cells.

Synonyms

  • B-cell-differentiating factor
  • B-cell growth factor[9]
  • T-cell growth factor.[10]


Clinical relevance

IL-4 is the main physiological regulator of allergic reactions. It plays a key role in contact sensitivity skin reactions.

Therapeutic implication

  • It is useful in the treatment of HIV
  • It has an antitumor effect on some solid tumors.


Periodontal implication

  1. It synergizes with IL-2 in terms of enhancing the generation of cells which kill the tumor cells
  2. IL-4 also suppresses IL-induced expression of Matrix Metalloproteinase-3 (MMP) in human gingival fibroblasts.


IL-4 inhibits the IL-1 induction of MMP-3 in human gingival fibroblasts isolated from patients with periodontitis.[8]

Chronic inflammatory periodontitis is characterized by enhanced levels of IL-1 β, tumor necrosis factor, and prostaglandin-E2. Surprisingly, there seems to be a local imbalance in T-cell, with a relative absence of IL-4-producing T-cells at sites of chronic inflammation. The imbalance is relatively progressive with the descending levels of IL-4 which are related to loss of collagen and escalating clinical severity. It is therapeutic only when the correction of cytokine imbalance is done in chronic inflammatory conditions, although a better understanding of beneficial effects of IL-4 might make safer and reasonable therapies.

Rheumatoid arthritis, periodontitis, and other chronic inflammatory conditions result in breakdown of tissue in big amount by local production of inflammatory mediators, including MMPs and prostaglandins. IL-4, an anti-inflammatory cytokine, has a dose-dependent inhibitory effect on the IL-1 and it induces MMP-3.[11]

Interleukin-5

Synonyms

Eosinophil differentiation factor.

Periodontal implication

High levels of IL-5, mRNA expression, have been found in mononuclear cells which are present in severe periodontal destruction. There is no clear-cut correlation as yet established.

Interleukin-6

Synonyms

  • β-2 interferon (IFN-b2)
  • Hybridoma/plasmacytoma growth factor
  • Hepatocyte-stimulating factor
  • B-cell stimulatory factor 2
  • B-cell differentiation factor.


IL-6 is a glycoprotein produced by a variety of cells including mononuclear phagocytes, T-cells, and fibroblasts.

Periodontal implications

Certain researchers reported that IL-6 levels were enhanced more in inflammatory gingiva than in healthy gingiva (Guillot et al. 1990). IL-6 was also detected in the GCF of periodontitis patients. Mathew et al. (1991) from the studies reported that IL-6 enhances the synthesis of collagen and glycolaminoglycans in dermal fibroblasts.

Spontaneous production of IL-6 in mononuclear cell isolates from inflamed gingiva has also been reported in various studies, but on the contrary, other studies suggest the role of immunoregulator cells such as lymphocytes and macrophages in producing IL-5 at inflammatory sites.

It has also been reported that IL-6 along with IL-1 b and TNF may influence gingival fibroblasts in the middle stages of periodontitis (Tsai et al. 1995).

IL-6 can induce IL-1 production from fibroblasts and osteoblast-like cells (Kishimato 1998).

Catabolic effects of IL-6 which may contribute to periodontal destruction are as follows:

  • Inhibition of fibroblast growth
  • Increasing number of osteoblasts
  • Inhibition of osteoblast alkaline phosphatase activity
  • Collagen synthesis.


IL-6 and IL-11 are allied cytokines but seem to have diverse functions in chronic periodontitis. In one of the studies, the systemic injection of IL-11 caused a significant decline in the level of bone as well as attachment levels compared to the control group. It is because of anti-inflammatory nature of IL-11.

Interleukin-7

IL-7-producing cells have been detected in the thymus and spleen. The study by Lee et al. shows that IL-7 is primarily a growth-promoting factor and is not involved in B-cell precursor differentiation. In addition to B-cell progenitor cells, T-cells are also responsive to IL-7. Its ramifications in periodontal disease are not yet clear.

Interleukin-8

Periodontal implication

Granulocyte accumulation is appropriately mediated by IL-8. It has been shown that IL-8 is primed by IL-1 β strikingly and upregulates neutrophil to release elastase, giving rise to a significant amplification of inflammatory response.

It has been detected in GCF (Payne et al. 1993) and gingival tissues of periodontal patients. It was 100% found in GCF of patients suffering from periodontitis and 75% detected in GCF of healthy patients.

Interleukin-9

Synonym

  • P40.


It is primarily derived from T-cells. It is a T-cell growth factor capable of sustaining permanent antigen-independent growth. It also appears to enhance the IL-8 stimulation and proliferation of bone marrow-derived mast cells.

Interleukin-10

Synonym

  • Cytokine synthesis inhibiting factor.


Its primary source is stimulated B-cell. Its major function is IL-2 and IL-4 proliferation from mature and immature thymocyte population. It inhibits cytokine production by activated T-helper clones.

Periodontal implication

Elevated levels of IL-10 have been linked in the pathogenesis of autoimmune diseases such as SLE, rheumatoid arthritis, and Sjogren’s syndrome. Investigators have shown in studies that IL-10 hampers the neutrophil activity of phagocytosis and is, by nature, bactericidal. An enhanced production of IL-10 in gingival tissue may suppress phagocytosis against periodontal pathogenic bacteria and escort to the progression of ailment.

Gamonal J. et al. (2000) showed that IL 10 was discovered solely in chronic periodontisis. IL 10 was found in pockets of periodontal patients and also it was found to be present in 43% of GCF samples, and a slight deviation was observed in active sites.[5]

Interleukin-11

IL-6 has a functional homolog which is IL-11. It can also replace IL-6 from the proliferation of certain plasmacytoma cell line. It also induces acute-phase protein secretion in the liver.

Stimulation of T-cell-dependent B-cell immunoglobulin secretion, increased platelet production, and induction of IL-6 expression by CD4+ T-cells are some additional IL-11 activities.

Interleukin-12

It is produced by phagocytic cells, B-cells, and other antigen-presenting cells. It is a potent inducer of cytokine production and causes T- and NK-cells to secrete IFN-γ.

Synonym

  • Cytotoxic lymphocyte maturation factor
  • T-cell-stimulating factor.


Periodontal implications

The pathological process of periodontitis is modulated by the immune system, which plays an important role. Monocytes, macrophages, and neutrophils produce IL-12. The high level of IL-12 causes the immune reaction in Th1 type. IL-12 is also activated by lipopolysaccharide. It has a role in the pathogenesis of periodontal disease but within the periodontitis sites. The IL-12 levels are found to increase in GCF of chronic periodontitis patients compared to healthy individuals.

Interleukin-13

It is a cytokine produced by activated T-lymphocytes.

Biological actions

IL-13 is a regulator of B-cells and monocyte activity.

Interleukin-14

T-lymphocytes and malignant B-lymphocytes secrete IL-14. It induces B-cell proliferation and inhibits immunoglobulin secretion.

Biological actions

  • Enhances the proliferation of activated B-cell
  • Hyperproduction of IL-14 together with IL-6 and IL-10 has been reported in systemic lupus erythematosus.


Interleukin-15

Mononuclear phagocytes release IL-15 with a key role in the promotion of NK-cell proliferation.

Periodontal implications

Maintenance of tissue homeostasis is taken care by apoptosis. Apoptosis mediators play an important role in the pathogenesis of drug-influenced gingival enlargement. IL-15 levels in GCF of cyclosporin A (CsA)-treated patients were measured and it exhibited significantly higher GCF levels of IL-15 compared to healthy controls. The pathogenesis of Cs-induced gingival overgrowth is multifactorial. It was found that IL-15 may play a role in the pathogenesis of Cs-induced gingival overgrowth due to its interaction with Cs and its role in inflammation and apoptosis.[12]

Interleukin-16

IL-16 can cause the high affinity of IL-2 receptors on CD4+ cells and is chemotactic to Th1 cells and CD4+ T cells. IL-16 can stimulate monocytes to produce pro-inflammatory cytokines and is highly associated with inflammation including arthritis, enteritis, and allergic rhinitis.[13],[14]

Synonym

  • Lymphocyte chemoattractant factor.


Periodontal implications

IL-16 may be related to periodontal disease severity in alcohol drinkers/smokers. The concentration and total amount of IL-16 both are raised in alcohol consumers and cigarette smokers with periodontal disease. Deeper probing pocket depths are found in alcoholics as well as smokers.

Interleukin-17

It is classified as pro-inflammatory cytokine because it induces many mediators of inflammation that are involved in proliferation, maturation, and chemotaxis of neutrophils. It is a new cytokine family secreted by activated CD-4 and CD-8 T-lymphocytes.

Periodontal implications

Clinical attachment levels positively affect gingival concentrations of IL-17. The gingival concentration of IL-17 was correlated significantly with IL-23, IL-1beta, IL-6, and TNF-alpha concentrations and negatively related to IL-12. The results suggest that within chronic inflammatory periodontal disease, IL-17 or IL-23 immune response was present. This kind of host response which has not been researched previously in chronic inflammatory periodontal disease and is an important factor.[13],[14]

Interleukin-18

It is structurally similar to IL-1 and functionally similar to IL-2. It increases the cytotoxic activity of NK-cells and T-lymphocytes and may play a role both as a neuroimmunomodulator and in the induction of mucosal immunity.

Interleukin-20

IL-20 is produced by activated keratinocytes as well as monocytes and it transmits an intracellular signal through two distinct cell-surface receptor complexes on keratinocytes and other epithelial cells.[15] As such, it is likely to have a central role in inflammatory skin diseases such as psoriasis and eczema.


  Summary and Conclusion Top


ILs play an extremely important role in forming a communication network that links inducer and effector cells during immune and inflammatory responses. These mediators also serve as recruitment signals for precursors of immune and inflammatory cells.

ILs play an important role in periodontal disease pathology. IL-1α is an active entity involved in bone resorption. IL-1 β has an important role in periodontal pathology due to its potency in inhibiting bone formation and enhancing bone resorption. It plays a pivotal role in inflammation cascade in response to bacterial lipopolysaccharide. It also induces MMP’s activity and prostaglandin synthesis and enhances protease activity in fibroblasts and osteoblasts.

Drug-induced gingival enlargements are influenced by IL-1 and IL-15. IL-1 β has a major link for phenytoin-induced gingival overgrowth. IL-15 plays an important role in apoptosis and inflammation in cases of Cs-induced gingival overgrowth.

IL-2 and IL-6 stimulate periodontal destruction and bone resorption. Inflammatory activity is increased by the interaction of IL-1 and IL-6 with a spectrum of inflammatory cell types. In addition, both of these ILs induce fever, an event that enhances the overall activity of immune and inflammatory cells.

IL-1-mediated MMP-3 is suppressed by IL-4 in fibroblasts of humans. It has been suggested that IL-4 is beneficial and therapeutic in chronic inflammatory conditions (like periodontal inflammation). Hence, it is an anti-inflammatory cytokine.[11]

IL-10 is involved in pathogenesis of autoimmune diseases like Sjogren’s disease.

IL-12 has been called as “jump starter of cell mediated immunity,” indicating that IL-12 acts early in infection.

In alcoholics and smokers, IL-16 had a role in the severity of periodontal diseases. Finally, we must expect that other, as yet unknown, ILs will be recognized and cause us to revise and refine our view of the IL communication network.[16],[17]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Disclosure

This material has never been published and is not currently under evaluation in any other peer reviewed publication.

Ethical approval

The permission was taken from Institutional Ethics Committee prior to starting the project. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.



 
  References Top

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Rosa MR, Pinto AM. Cytokines. In: Burtis CA, Ashwood ER, Bruns DE, editors. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics-e-Book. St.Louis Missouri: Elsevier Health Sciences; 2012. p. 645-744.  Back to cited text no. 1
    
2.
Mota FV, de Araújo Neta MS, de Souza Franco E, Bastos IV, da Araújo LC, da Silva SC, et al. Evaluation of anti-inflammatory activity and molecular docking study of new aza-bicyclic isoxazoline acylhydrazone derivatives. Medchemcomm 2019;10:1916-25.  Back to cited text no. 2
    
3.
Kirkwood KL, Nisengard RJ, Haake SK, Miyasaki KT. Immunity and Inflammation: Basic concepts. In: Newman MG, Takei HH, Klokkevold PR, Carranza FA, editors. Carranza’s Clinical Periodontology. 10th ed. Missouri, Saunders: First Printed in India; 2007. p. 209-25.  Back to cited text no. 3
    
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Carol & Richard Eustice. What are Cytokines? Available from: http://www.arthritis.about.com/Updated:February6,2008(About.com Health’s Disease and Condition content is reviewed by the Medical Rev iew Board). [Last accessed on 2009 Feb 01].  Back to cited text no. 4
    
5.
Gamonal J, Acevedo A, Bascones A, Jorge O, Silva A. Levels of interleukin‐1β, 8, and‐10 and RANTES in gingival crevicular fluid and cell populations in adult periodontitis patients and the effect of periodontal treatment. J Periodontol 2000;71:1535-45.  Back to cited text no. 5
    
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Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci 1997;2:d12-26.  Back to cited text no. 6
    
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Gilman A, Goodman LS, Hardman JG, Limbird LE. Goodman & Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2001.  Back to cited text no. 7
    
8.
Faizuddin M, Bharathi SH, Rohini NV. Estimation of interleukin-1b levels in the gingival crevicular fluid in health and in inflammatory periodontal disease. J Periodontal Res 2003;38:111-4.  Back to cited text no. 8
    
9.
Oliver K, Noelle RJ, Uhr JW, Krammer PH, Vitetta ES. B-cell growth factor (B-cell growth factor I or B-cell-stimulating factor, provisional 1) is a differentiation factor for resting B cells and may not induce cell growth. Proc Natl Acad Sci U S A 1985;82:2465-7.  Back to cited text no. 9
    
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Available from: https://en.m.wikipedia.org>wiki; T cell growth factors. [Last accessed on 2020 Feb 02].  Back to cited text no. 10
    
11.
Jenkins K, Javadi M, Borghaei RC. Interleukin-4 Suppresses IL-17-induced expression of matrix metalloproteinase-3 in human gingival fibroblasts. J Periodontol 2004;75:283-91.  Back to cited text no. 11
    
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Buduneli E, Genel F, Atilla G, Kütükçüçler N. Evaluation of p53, bcl-2, and interleukin-15 levels in gingival crevicular fluid of cyclosporin A-treated patients. J Periodontol 2003;74:506-11.  Back to cited text no. 12
    
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Lester SR, Bain JL, Johnson RB, Serio FG. Gingival concentrations of interleukin-23 and-17 at healthy sites and at sites of clinical attachment loss. J Periodontol 2007;78:1545-50.  Back to cited text no. 13
    
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Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K, Collins M, et al. Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 2006;203:2271-9.  Back to cited text no. 14
    
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Rich BE, Kupper TS. Interleukin 20. Anti inflammatory & anti allergy agents in medicinal chemistry. Current Medicinal Chemistry Anti Inflammatory and Anti Allergy Agents 2006; 5:243-50.  Back to cited text no. 15
    
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Available from: http://www.copewithcytokines.de/. [Last accessed on 2009 Feb 01].  Back to cited text no. 16
    
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Available From: http://en.wikipedia.org/wiki/interleukin. [Last accessed on 2009 Feb 02].  Back to cited text no. 17
    


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Introduction
Cytokines
Interleukins
Various Interleu...
Summary and Conc...
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