The Overview of Interleukin


View:220 Time:2018-06-07


1. What is Interleukin

Interleukin is a kind of cytokines, which plays a critical role in immunological regulation and homeostasis. It is originally discovered from leukocytes. Currently, it is found to be produced by a lot of cells including macrophages, lymphocytic cells with a solid structure and function.

2. Interleukin Family and Interleukin Receptor

The members of interleukin are wealthy which are named IL-1~IL-38.

The interleukin receptors can be classified as type I, type II and other type. The type II interleukin receptors include interleukin-10, 20, 22, 28 receptors, the other types include interleukin-1,8 receptors, the rest of them are type I interleukin receptors.

Table 1. Interleukin Family and Receptors

Gene Name/Alias Uniprot ID Receptors
IL-1 α P01583 IL1R1, IL1R2
IL-1 β P01584 IL1R1, IL1R2
IL-2 P60568 IL2RA, IL2RB, IL2RG
IL-3 P08700 IL3RA, IL3RB
IL-4 P05112 IL4R
IL-5 P05113 IL5RA, IL3RB
IL-6 P05231 IL6R
IL-7 P13232 IL7R
IL-8 P10145 IL8RA, IL8RB
IL-9 P15248 IL9R
IL-10 P22301 IL10RA
IL-11 P20809 IL11RA
IL-12 α P29459 IL12RB1
IL-13 P35225 IL13RA1, IL13RA2
IL-14 P40222 Unkown
IL-15 P40933 IL15RA
IL-16 Q14005 CD4
IL-17 α Q16552 IL17RA
IL-18 Q14116 IL18R1
IL-19 Q9UHD0 IL20R
IL-20 Q9NYY1 IL20R
IL-21 Q9HBE4 IL21R
IL-22 Q9GZX6 IL22RA1
IL-23 Q9NPF7 IL23R
IL-24 Q13007 IL20R
IL-25 Q9H293 LY6E
IL-26 Q9NHP9 IL20R1
IL-27 α Q8NEV9 IL27RA
IL-27 β Q14213 IL27RA
IL-28 Q8IU57 IL28R
IL-29 Q8IU54 Unknown
IL-30 Q8NEV9 Unknown
IL-31 Q6EBC2 IL31RA
IL-32 P24001 Unknown
IL-33 O95760 Unknown
IL-35 Q14213 Unknown
IL-36 α Q9UHA7 Unknown
IL-36 β Q9NZH7 Unknown
IL-36 γ Q9NZH8 Unknown

3. Common Signaling Pathway

IL-1 Pathway

There are 11 members in this family. They (IL-1, 18, 33, 36, 37, 8) bind to IL1,18 primary receptors. IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ triggers MPKK and NF-κB leading to inflammatory response. While other members of IL-1 family have anti-inflammatory effects. IL-1 is one hallmark cytokine in this family which can excert as co-stimulation of T helper cells, maturation and proliferation of B cells, activation of NK cells and is relation to inflammation.

IL-10 Pathway

IL-10 is an important anti-inflammatory cytokine which is produced by activated T cells, B cells, macrophages and monocytes. It involves in cytokine production of macrophages, activation of B cells, stimulation of Th2 cells, meanwhile, it inhibits cytokine production of Th1 cells. It can form a homodimer that binds to the tetrameric heterodimer IL-10 receptor and inhibit the IL-1, IL-6 and TNF pathway. It is related with non-small scell lung cancers.

IL-12 Pathway

There are 4 members in this family. It (IL-12, 25, 27, 35) belongs to IL-6 superfamily is a special family as it is formed by heterodimers. It mediates phosphorylation of SAT1,3,4 by the JAK/STAT family. IL-12 involves in the stimulation and maintenance of Th1 cellular immune responses, including the normal host defence against various intracellular pathogens.

IL-17 Pathway

There are 6 members of the IL-17 family, and 5 members in its receptor family. It plays critical roles in host immunology. IL-17A is the hallmark in this family that it protects the host against extracellular pathogens, but also promotes inflammatory pathology in autoimmune disease, similar to IL-17C. While IL-17F involves in the mucosal host defense, IL-17E amplifies the Th2 immune response. The IL-17 family activates antibacterial cytokines and chemokines in MAPK, NF-κB and C/EBPs pathway. Act1 is considered as the master mediator in this pathway.

IL-7 Pathway

IL-7 is a kind of glycoprotein which is produced by bone marrows and weighs 25KDa. It is produced primarily by stromal cells and exerts its effects through a receptor complex consisting of IL-7 R alpha and common gamma-chain/IL-2 R gamma. As one of the hematopoietic growth factor, it stimulates the differentiation of multipotent hematopoietic stem cells into lymphoid progenitor cells, and also stimulates the proliferation of lymphoid cells. Additionally, IL-7 can increase the T effector numbers such as CD4 T cells, CD8 T cells, naive T cells and B cells, and then infiltrate organs like liver, kidney and brain[1].

4. Interleukin Function

Interleukin is important for transmitting information, activating and regulating immune cells, mediates the activation, proliferation and differentiation of T cells and B cells.

Interleukin-1 contains IL-1α and IL-1β. While the former is produced by diverse cells, the later is produced by some specific tissues. IL-1β is cleaved by caspase-1 which is formed by proteins termed as “the inflammasome”. It can lead to pain and short-time sleep, so that they study the relationship between fatigue and IL-1[2]. IL-1 also can simulate the nitric oxides, chemokines, cytokines and ahesion molecules that destroy the cartilage, while the IL-1 receptor antagonist can inhibit the destruction of IL-1 through the completion of the same receptor. The study helps us to understand the pathology of these diseases[3].

Interleukin-2 is popular object in the past 36 years as it is important for the immunotherapy of many diseases including cancers. But the adverse of taking it is fearful[4].Thus, timing of IL-2 administration and different T cells status are crucial to IL-2 therapies[5].

Interleukin-10 is an anti-inflammatory cytokine. In the meanwhile, IL-10 suppresses the immune responses by modulating the T cells and antigen-presenting cells. By controlling the receptor of IL-10, we can resolve the chronic viral infection[6]. The research was published in The Journal of Experimental Medicine in 2006.

Interleukin-18 is a regulator of cancer and autoimmune diseases. As a member of IL-1 family, it plays essential roles in inflammation process. It can cooperate with IL-12 to activate cytotoxic T cells (CTLs) and natural killer (NK) cells to produce IFNγ which may contribute to tumor immune. In addition, it can work with IL-23 to induce the secretion of IL-17. It has pros and cons effects in the treatment of many diseases[7].

5. Interleukin and Inflammation

Inflammation is a productive conduct to stimuli such as pathogens and damage cells. Its characters are heating, redness, swelling, pain and loss of function, sometimes accompanied with fever. Inflammasome activation leads to activation of caspase-1, resulting in the induction of apoptosis and the secretion of pro-inflammatory cytokines including IL-1β and IL-18[8]. Without inflammation, we can not prevent harm from stimuli, but it can lead to chronic infection such as rheumatoid arthritis. Inflammation plays a key role in chronic inflammatory systemic diseases (CISD). There are overlaps between different CISD.

a. Interleukin-17 and Psoriasis

Psoriasis is a common, infammatory and chronic disease with the character of erythematous, scaly plaques. It is related to cardiovascular disease (CVD) such as artherosclerosis. As a result of immune dysregulation, its pathology refers to infammatory cytokines like tumor necrosis factor (TNF), interferon (IFN) and IL-1β, IL-6, IL-12, IL-17, IL-22, IL-23 produced from dendritic cells, T-helper cells and keratinocytes. Patients with psoriasis have more Th17 cells and higher level of IL-17A mRNA and protein. The recent study demonstrates over-expressing IL-17 causing increased inflammatory cells and levels of nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO) makes more severe psoriasis, and endothelial dysfunction. In contrast, blocking of IL-7 or the genes acting downstream of IL7 improve the severity of psoriasis[8][9].

b. Interleukin and Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a severe autoimmune disease accompanied with cartilage degradation, joint destruction and poor prognosis[8]. The study indicates that the polymorphism of inflammation genes leads to the susceptibility of RA[10][11][12]. Caspase-1 is a critical factor of RA, we can observe the reduction of RA in the caspase-1-/- mice model[13]. Another member is NLRP1 which is related to the secretion of IL-1β and IL-18. Inhibiting the NLRP1 can ameliorate the symptom of RA[14].

c. Interleukin and Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE), accompanied with inflammatory joints, nephritis, mouth ulcer, swollen lymph nodes and butterfly-shaped red rash on the face, is a rare inflammatory rheumatic disease that attacks normal healthy tissues in the body. The major representation is lupus nephritis (LN) with severe kidney destruction. The study explains the relationship between the expression of inflammasome and LN[15]. Tsai et al reported inhibiting the expression of mRNA and production of IL-1β, IL-18, caspase-1 relieves the symptom of LN[16]. Ka et al further reported that a main active ingredient in the herbal medicine Litsea cubeca, significantly inhibited activation of NLRP3 inflammasome and caspase-1 and the secretion of IL-1. Moreover, it effectively ameliorated LN symptoms in accelerated and severe LN mice[17].

d. Interleukin and Crohn's Disease

Crohn’s disease (CD) is a chronic inflammatory condition of the GI tract with no known cure. It is demonstrated efficient to take antibody-based therapies directed against TNF or interleukin-12/interleukin-23 p40 subunit antibody or integrins in moderate-to-severe CD. However, many patients experience primary non-response or lose response over time to anti-TNF therapy, so that we require dose adjustment, or switch to a non-anti-TNF therapy. Interleukin-6 has multiple pro-inflammatory effects such as inhibition of apoptosis in T-cells and is a target for curing CD. A recent study of the IL-6 receptor inhibitor, tocilizumab, manifests a clinical benefit in moderate-to-severe CD[18].

References

[1]Pellegrini M, Calzascia T, et al. IL-7 Engages Multiple Mechanisms to Overcome Chronic Viral Infection and Limit Organ Pathology[J]. Cell, 2011(144): 601-603

[2]Megan E. Roerink, Marieke E. van der Schaaf, et al. Interleukin-1 as a mediator of fatigue in diseases: a narrative review[J]. Journal of Neuroinflammation, 2017(14): 16

[3]Claire J, Marjolaine G, et al. The role of IL-1 and IL-1Ra in joint inflammation and cartilage degradation[J]. Vitamins and Hormones, 2006(74): 371-403

[4]Dhupkar P, Gordon N. Interleukin-2: old and new approaches to enhance immune-therapeutic efficacy[J]. Adv Exp Med Biol, 2017(995): 33-51

[5]Blattman JN, Grayson JM, et al. Therapeutic use of IL2 to enhance antiviral T-cell responses in vivo[J]. Nat Med, 2003(9): 540-547

[6]Eirnaes M, Filippi CM, et al. Resolution of a chronic viral infection after interleukin-10 receptor blockade[J].J Exp Med, 2006(203): 2461-2472

[7]Esmailbeig M, Ghaderi A. Interleukin-18: a regulator of cancer and autoimmune diseases[J]. Eur Cytokine Netw, 2017(28): 127-140

[8]Yi YS. Role of inflammasomes in inflammatory autoimmune rheumatic diseases[J]. Korean J Physiol Pharmacol, 2018(1): 1-15

[9]Lockshin B, Balaqula Y, et al. Interleukin-17, inflammation, and cardiovascular risk in patients with psoriasis[J]. J Am Acad Dermatol, 2018, accepted

[10]Mathews RJ, Robinson JI, et al. Evidence of NLRP3-inflammasome activation in rheumatoid arthritis (RA); genetic variants within the NLRP3-inflammasome complex in relation to susceptibility to RA and response to anti-TNF treatment)[J]. Ann Rheum Dis, 2014(73): 1202-1210

[11]Jenko B, Praprotnik S, et al. NLRP3 and CARD8 polymorphisms influence higher disease activity in rheumatoid arthritis)[J]. J Med Biochem, 2016(35): 319-323

[12]Sui J, Li H. NLRP1 gene polymorphism influences gene transcription and is a risk factor for rheumatoid arthritis in han chinese. Arthritis Rheum, 2012(64): 647-654

[13]Joosten LA, Netea MG, et al. Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1)[J]. Arthritis Rheum, 2009(60): 3651-3662

[14]Zhang L, Dong Y, et al. Hydroxysteroid dehydrogenase 1 inhibition attenuates collagen-induced arthritis)[J]. Int Immunopharmacol, 2013(17): 489-494

[15]Roberts TL, Idris A, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA)[J]. Science, 2009(323): 1057-1060

[16]Tsai PY, Ka SM, et al. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation)[J]. Free Radic Biol Med, 2011(51): 744-754

[17]Ka SM, Lin JC, et al. Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation)[J]. Arthritis Res Ther. 2015(17): 331

[18]Danese S, Vermeire S, et al. Randomised trial and open-label extensive study of an anti-interleuki8n-6 antibody in crohn's disease(ANDANTW I and II)[J]. Gut, 2017, doi:10.1136

 

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