Overview of Interleukins

Since the discovery of IL-1 in 1977, approximately 200,000 published articles have referred to ILs. The name “interleukin” was chosen in 1979, to replace the various different names used by different research groups to designate interleukin 1 (lymphocyte activating factor, mitogenic protein, T-cell replacing factor III, B-cell activating factor, B-cell differentiation factor, “Heidikine”).Secreted proteins that bind to their specific receptors and play a role in the communication among leukocytes are named ILs. ILs are assigned to each family based on sequence homology and receptor chain similarities or functional properties. Usually, ILs contain the following families:

IL-1 Family
IL-6 Family
IL-10 Family
IL-12 Family
IL-17 Family
Other Interleukins

 

cytokine-interleukins-overview

Introduction of Type II Interferon

Type II interferon Unlike the type I IFNs, which all appear to signal as monomeric cytokines, IFNγ signals as an anti-parellel homodimer. The complex through which this cytokine signals is composed of four transmembrane-spanning receptors; two chains of each of the high-affinity(IFNGR1) and low-affinity receptors (IFNGR2). The IFNγ homodimer engages directly with the two IFNGR1 chains on opposing sides of the cytokine dimer. IFNGR1 has been shown to be pre-associated with IFNGR2 and although the ligand does not engage IFNGR2 directly, ligand-induced conformational changes in both receptors have been reported. Despite the fact that both IFNGR1 and IFNGR2 are not always present together on the surface of all cells, both receptor components are required for full activity of IFNγ. For signal transduction via the JAK/STAT pathway, IFNGR1 binds to JAK1 whereas IFNGR2 binds to JAK2. Although both kinases are necessary for signal transduction, only JAK1 has been demonstrated to be required for the formation of the full IFNγ signaling complex.

Fig.Activation of phosphatidylinositol 3-kinase and protein kinase C- by the type II interferon receptor and crosstalk with the STAT-signalling pathway.
Fig.Activation of phosphatidylinositol 3-kinase and protein kinase C- by the type II interferon receptor and crosstalk with the STAT-signalling pathway.

Introduction of Type I Interferon

Type I interferons are a large group of structurally similar cytokines, in humans including more than 13 different members of IFNα as well as IFNβ, IFNε, IFNκ and IFNω. The genes encoding type I interferons are clustered in one locus on the same chromosome (chromosome 9 in humans and chromosome 4 in mice), and they have been suggested to have diverged from a common ancestor, with the IFNβ gene being the primordial gene. Despite their seemingly broad range of amino-acid homologies, all type I IFNs signal through a common heterodimeric receptor composed of low- (IFNAR1) and high-affinity (IFNAR2) receptor components.

More than 50 years after their discovery, type I interferons have been included in our therapeutic armamentarium and are indicated for several disease entities. Firstly, type I interferons are widely used for the treatment of chronic viral infections, mainly by hepatitis B virus and hepatitis C virus. Type I interferons have also been used in the treatment of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), with more success in animal models than in the clinic. In addition to the above-described beneficial effects in infections, in malignancies and in some autoimmune/inflammatory diseases, there is evidence that type I interferons can also be detrimental for the host by promoting autoimmunity, inflammation and interferon treatment-related toxicities in a context-dependent manner.

Fig. Multiple signaling pathways mediated by Type I IFN.
Fig. Multiple signaling pathways mediated by Type I IFN.

Overview of Interferons

In studying the phenomenon of viral interference, Isaacs and Lindenmann discovered interferon in 1957. On the basis of this criteria the IFNs were initially classified into two types—the type I family composed of the acid-stable forms IFNα and IFNβ, whereas the acid-labile form, IFNγ, was classified as the lone type II IFN.2 In recent years, a third type of IFN has been described, IFNλ. Originally termed interleukin (IL)-28a/b and IL-29 these proteins have been re-classified as IFNs based on the similar modes of induction and anti-viral activities they share with the type I and type II IFNs. However, although the type I and type III IFNs are induced during a viral infection and are, at least in part,involved in host defense against viruses, the type II IFN is primarily involved in the allergic response, in host defense against intracellular pathogens and in control of tumors.

Ligand types Names Receptor chain 1 Receptor chain 2
Type I IFN IFN-αIFN-βIFN-εIFN-κ

IFN-ω

IFN-υ

IFN-αR1(Also IFN-αRα, IFNAR1) IFN-αR2(Also IFN-αRβ,IFNAR2)
Type II IFN IFN-γ IFN-γR1(Also IFN-γRα, IFNGR1) IFN-γR2(Also IFN-γRβ,IFNGR2)
Type III IFN IL-28AIL-28BIL-29 IL-28R1 IL-10R2

Interleukin-17 (IL-17) family

The IL-17/IL-17 receptor family is the newest and least understood of the cytokine subclasses.

Composed of ligands IL-17A-IL-17F and receptors IL-17RA-IL-17RE, these cytokines have many

unique structural and functional features. Members of this family have a highly conserved C-terminus containing a cysteine-knot fold structure. Most IL-17 proteins are secreted as disulfide-linked dimers, with the exception of IL-17B, which is secreted as a non-covalent homodimer.

Interleukin, IL-17 Receptor Family
Interleukin, IL-17 Receptor Family

Interleukin 12 (IL-12) family

The interleukin 12 (IL-12) family is unique in having the only heterodimeric cytokines, including IL-12, IL-23, IL-27 and IL-35. This family also has many molecular and functional characteristics that provide unique opportunities for positive and negative feedback control, and some additional features may still be identified. IL-12 is composed of p35 and p40 subunits. IL-23 is composed of the IL-12p40 subunit and the IL-23p19 subunit, which shares homology with IL-12p35. IL-27 is composed of EBI3/IL-27B and p28. IL-35, a novel member of IL-12 family, is composed of the IL-12p35 and EBI3 subunits. IL-35 is secreted by regulatory T cells, and suppresses inflammatory responses of immune cells.

Interleukin, IL-12 Receptor Family
Interleukin, IL-12 Receptor Family

Interleukin-10 (IL-10) family

The IL-10 superfamily is highly pleiotropic. Its members are linked together through genetic similarity and intron-exon gene structure. Significant commonality exists not only through shared

receptors but also through conserved signaling cascades. However, its members mediate diverse activities, including immune suppression, enhanced antibacterial and antiviral immunity, antitumor activity, and promotion of self-tolerance in autoimmune diseases.

Interleukin, IL-10 family
Interleukin, IL-10 family

Interleukin-6 (IL-6) family

IL-6, IL-11, IL-31 belong to the IL-6 family of cytokines. Inclusion in the IL-6 family is based on a helical cytokine structure and receptor subunit makeup. Members of the IL-6 family of cytokines activate the signal transducing receptor protein, glycoprotein 130 (gp130). As they share a common signal transducer, IL-6 family cytokines display both unique and overlapping biologic activities on multiple hematopoietic lineages. IL-6 family binding to the gp130 alpha subunit induces homodimerization and subsequent activation of Janus kinases (JAK), followed by activation of signal transducers and activators of transcription (STAT1 and STAT3).

Interleukin, IL-6 Receptor Family
Interleukin, IL-6 Receptor Family

Interleukin-1 (IL-1) family

The Interleukin 1 (IL-1) family is a group of 11 cytokines, which plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. All of the members of IL-1 family, except of IL-1Ra, are first synthesized as a precursor protein, which means it is synthesized as a long form of protein which has to be proteolytically cleaved to a shorter, active molecule, which is generally called mature protein. IL-1 family precursors do not have a clear signalpeptide for processing and secretion and none of them are found in the Golgi, they belong to so-called leaderless secretory protein group. The similar feature of IL-1α and IL-33 is that their precursor forms can bind to their respective receptor and can activate signal transduction. But this is not a common feature for all IL-1 family members, since IL-1β and IL-18 precursor forms do not bind their receptors and require proteolytic cleavage by either intracellularcaspase-1 or extracellular neutrophilic proteases.

Interleukin, IL-1 family
Interleukin, IL-1 family

Introduction of Cytokines

Cytokines, a large group of soluble extracellular proteins or glycoproteins, are key intercellular regulators and mobilizers. Cells of the immune system communicate with one another by releasing and responding to chemical messengers called cytokines. These proteins are secreted by immune cells and act on other cells to coordinate appropriate immune responses. They are now seen to be crucial to innate and adaptive inflammatory responses, cell growth and differentiation, cell death, angiogenesis and developmental as well as repair processes.

cytokines classification
cytokines classification

CYTOKINES CAN ACT AS: 

  1. Mediators of the innate immunity (inflammation, chemotaxis, macrophage activation, NK cells) and adaptive immunity (humoral and cellular).  
  1. Regulators of lymphocyte activation, proliferation and differentiation. 
  1. Stimulators of the growth of hematopoietic stem cells.

 

Time line of milestones in cytokine biology
Time line of milestones in cytokine biology