Cytokines in dermatology - a basic overview.

Cytokines are non-immunoglobulin proteins and glycoproteins produced by a wide variety of cells, in response to any immune stimulus. Cytokines are signaling molecules that send downstream signals to various cells through a number of signal transduction pathways and act further by binding to specific membrane receptors (cytokine receptors) on the cell surface. They are emergency molecules, which are released transiently. Cytokines play an important role in cellular communication. They regulate immunity, inflammation, cell activation, cell migration, cell proliferation, apoptosis, and hematopoiesis. However, when released persistently they can produce chronic disease.

Introduction

Cytokines are signaling water soluble non-immunoglobulin proteins and glycoproteins with a mass of 8 to 30 kd, produced by a wide variety of cells including B and T lymphocytes, macrophages, endothelial cells, fibroblasts, mast cells, and stromal cells of the spleen, thymus, and bone marrow de novo, in response to any immune stimulus.[12] Although released transiently in the tissue microenvironment, as diverse, emergency molecules, they can produce chronic disease when released persistently.[3]

Cytokines play an important role in cellular communication and their function may be autocrine (if the cytokines act on the cell that secretes them), paracrine (if the action is restricted to the immediate vicinity of a cytokine's secretion) or endocrine (if the cytokine diffuses to distant regions of the body via blood or plasma to affect different tissues). They differ from hormones that are produced by endocrine glands and are not always proteins.[4]

Functionally cytokines have a wide range of activities. They generally act over short distances and short time spans and at a very low concentration. They regulate immunity, inflammation, cell activation, cell migration, cell proliferation, apoptosis, and hematopoiesis. They are critical to the functioning of both innate and adaptive immune responses and play a vital role in the development of the immune system. They are important factors in the cell-to-cell communication necessary for regulation of inflammatory responses and immune reactions, regulation of lymphocyte activation, proliferation, differentiation, and also stimulation of growth of hematopoietic cells.[5]

Cytokines send downstream signals to various cells through a number of signal transduction pathways They bind to specific membrane receptors on the cell surface, and as a result, set off a cascade of cytokines, which then signal the cell via second messengers to alter its behavior by causing induction or inhibition of downstream pathways.[6] This results in pleiotropism (multiple effects on a single cell or different set of effects on different cells) and redundancy (many cytokines send signals to the same class of receptors, by using similar signal transduction pathways, causing overlapping of biological effects, so that the absence of one can be compensated by others).[7] Responses to cytokines include increasing or decreasing the expression of membrane proteins (including cytokine receptors), proliferation, and secretion of effector molecules. Cytokines can also act synergistically (two or more cytokines acting together) or antagonistically (cytokines causing opposing activities).[8]

Signal Transduction Pathways

Cytokines use several downstream pathways to mediate their effects — The two most important pathways are the JAK-STAT pathway and the NF-kB pathway.[2] The other major signaling pathways are the Ras; Erk MAP kinase; PI 3 kinase; Phosphorylase C; IRS 1, and 2;Src family tyrosinase kinases, and the Sphingomyelinase ceramide pathways.[6]

JAK-STAT pathway

When a cytokine binds to its receptor at the cell surface dimerization of the receptor and activation of receptor-associated JAKs take place, resulting in the activation of signaling. The receptor is phosphorylated by the activated JAK, creating binding sites for STATs, which are also phosphorylated by JAK. The phosphorylated STAT proteins dimerize and are transported to the nucleus where they induce the transcription of many cytokine-regulated genes.[9] This pathway can be suppressed by three mechanisms — SHP-1, PIAS, and SOCS proteins.[10]

NF-kB pathway

There are 84 key genes related to the NFκB-mediated signal transduction. These include genes that encode members of the Rel, NFκB, and IκB families, NFκB-responsive genes, extracellular ligands, and receptors that activate the pathway, and the kinases and transcription factors that propagate the signal. IL1, TNFα, IL17, and IL18, after using different cytokine receptors and proximal signaling pathways, activate the NFκB transcription factor and share the use of the NFκB pathway. Stimuli that can activate the NFκB signal transduction pathway are bacterial products, activators of protein kinase, ultraviolet rays, viruses, and oxidants. The NFκB-mediated signal transduction plays a significant role in inflammatory responses, apoptosis, viral replication, autoimmune diseases, and tumor formation.[11]

Cytokine Receptors

Cytokines act on their target cells by binding to specific cytokine receptors on the cell surface. These receptors are membrane glycoproteins consisting of several units. Recently soluble receptors for different cytokines have been found in the sera; they are similar to the membrane receptors and are found in large quantities.[12] It is thought that their function is to regulate cytokine production and to act as antagonists of the membrane receptors.

Classification of cytokines (according to receptors)

The different cytokine families are grouped in accordance to their receptor type

Class I cytokines (Hematopoietin receptor family)

They have receptors α, β, and γ. They are mostly multiple-chain receptors consisting of a cytokine-specific α subunit paired with one or more shared subunits. The shared subunits are:[1314]

Common γ (γc) chain (ILRG shared): shared by IL-2, IL-4isoform1, IL-7, IL-9, IL-15, and IL-21 receptors

IL13 RA1 shared: shared by IL-4 isoform 1, and IL-13

IL12RB1 shared: shared by interleukin 12A, interleukin 23, and alpha subunit p19

IL3RB (CSF2RB) shared: shared by colony stimulating factor 2, interleukin 3, and interleukin 5

Common β chain: shared by IL-2 and IL-15 receptors

IL-3-receptor β chain: shared by IL-3, IL-5, and GM-CSF receptors

IL-12Rβ2 chain: shared by IL-12 and IL-23 receptors

Gp 130 shared: shared by IL-6, IL-11, IL-27, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, cardiotrophin-1 receptor, and cardiotrophin-like cytokine factor 1

Others: Colony stimulating factor 3 isoform a, erythropoietin, growth hormone 1 isoform 1, growth hormone 2 isoform 1, leptin, prolactin, thymic stromal lymphopoietin isoform 1, and thyroid peroxidase isoform a

Class II cytokines (interferon / IL-10 receptor family)

Type I Interferons: IFNα family, IFNβ, IFNκ IFNω, and Limitin

Type II Interferons: IFNγ

IL-10 is the prototypic member of the IL-10 cytokine family and includes, IL10, IL19 isoform2; IL20; IL22; IL24 isoform1; IL26 (AK155); IL28A; IL28B; and IL29

TNF receptor family

TNFα (Cachectin); TNF ligand superfamily member 4,7,8,9,10,11. 12, 13 isoform alpha proprotein, 13b, 14 isoform 1precursor; 18; Lymphotoxin α; Lymphotoxin β; Fas ligand; CD40 ligand; and ectodysplasin A isoform EDA-A2

IL-1 receptor family

IL1α; IL1 β; IL16; IL18 (also IL1ra; and IL-1F5, through F10)

IL-17 receptor family

IL-17; IL-17B; IL17-C, IL17-D; IL17-E (IL-25); IL17-F; and IL-32

TGFβ receptor family

TGF β3, TGF β2, TG β1, Inhibinβ C chain preproprotein, Inhibinβ B subunit, Inhibinβ A, growth differentiation factor 5 preproprotein, bone morphogenetic protein 7,anti-Mullerian hormone, and activin β E

Chemokines receptor family

Subfamilies C, CC, CXC, and CX3C

PDGF family

Colony stimulating factor 1 isoform a; epidermal growth factor, fms-related tyrosine kinase 3 ligand, hepatocyte growth factor isoform 1 preproprotein, KIT ligand isoform b, PH domain-containing protein, platelet-derived growth factor beta isoform 1 preproprotein, platelet-derived growth factor C, vascular endothelial growth factor B, vascular endothelial growth factor C preproprotein, and vascular endothelial growth factor isoform a

Cytokines that Play an Important Role in Dermatology

Interleukin -1 receptor family[15] (IL-1, IL-18, IL-33)

IL-1 is a pro-inflammatory primary cytokine. It links the innate and acquired immune systems to provide synergistic host defense activities in the skin.[16] There are two forms of IL-1 — IL-1α and IL-1β. Although both molecules are present in the cytoplasm of cells and have a mass of 31 kd there are two major differences between them. IL-1α is inherently, biologically active, and is present in cells of the body that are in contact with the external environment. In the skin they are present in the epithelial cells. When the skin is injured, the keratinocytes release IL-1α and initiate inflammation.[17] However, if there is no injury then the epidermal turnover ensures that IL-1α is released into the environment. On the other hand, IL-1β has to be cleaved by Caspase-1 before it becomes biologically active. It is produced by cells such as Langerhans cells, monocytes, and macrophages, which are not regularly in direct contact with the external environment.[16] IL-1R1 is the only signal transducing receptor for IL-1 — active forms of IL-1 bind with it to induce inflammation. A molecule known as IL-1ra (IL-1 receptor antagonist) competes with IL-1 for receptor binding to IL-1R and acts as an antagonist to IL-1R ligand. Hence, the probable function of Il-1ra is to antagonize the IL-1 mediated inflammatory response.[2]

The role of IL-1 in the koebner phenomenon

In response to any mechanical stress or injury, keratinocytes release IL1, which in turn cause the release of ICAM-1, VCAM-1, E-selectin, and other cytokines, which attract certain memory T-cells bearing cutaneous lymphocyte antigen (CLA) on their cell surface. These memory T cells are present abundantly in inflamed skin and are attracted to any site of subsequent skin injuries. They are immediately activated if they recognize the antigens present at the site of inflammation causing release of pro-inflammatory cytokines, which magnify the inflammatory response resulting in the Koebner phenomenon.[18]

IL-18 is produced by keratinoytes, Langerhans cells, and monocytes. The specific receptor for IL-18 is IL-18R1. It acts on Th1 cells and NK cells, to induce their proliferation and production of cytokines such as IFNγ.[1920] IL-33 is structurally closely related to IL-1β and IL-18. It is expressed in keratinocytes, monocytes, and mast cells, and is upregulated when these cells are exposed to pro-inflammatory stimuli. It stimulates NF-κB and MAP kinases in the responsive cells, causing production of Th2 cytokines from the T cells.[1921]

TNF Receptor Family

The Tumour Necrosis Factor (TNF) is a cytokine involved in systemic inflammation and is a member of a group of cytokines that stimulate the acute phase reaction.[22] There are two structurally and functionally homologous forms — TNFα and TNFβ (formerly known as lymphotoxin α)

TNFα is produced in the skin by keratinocytes, melanocytes, Langerhans cells, activated T cells, NK cells, and mast cells. A metalloproteinase known as TACE (TNFα converting enzyme) is necessary for the release of TNFα from the T cells. The principal role of TNF is the regulation of immune cells. It causes inflammation, apoptotic cell death, cell proliferation, differentiation, tumorigenesis, and viral replication in various types of cells.[23] There are two types of TNF receptors — TNFR1 (CD120a, p55 / 60 receptor), which plays a more dominant role and TNFR2 (CD 120b, p75 / 80). Even as TNF-R1 is expressed by most tissues TNF-R2 is only found in cells of the immune system. TNFR1 can be fully activated by both the membrane-bound and soluble trimeric forms of TNF, while TNF-R2 only responds to the membrane-bound form of the TNF homotrimer.[24] TNF cytokine signaling occurs through three major pathways (a) NF-kB pathway — activation of this pathway enables the transcription of a vast array of proteins involved in inflammatory response (including the upregulation of adhesion molecules and induction of secondary cytokines and chemokines), cell survival and proliferation, and release of anti-apoptotic factors. (b) MAPK pathways (principally the JNK pathway) — activation of this pathway results in cell differentiation, proliferation, and apoptosis (c) Induction of death signaling through the death domain is present on TNFR1, but absent in TNFR2 — this signaling as well as interactions with other proteins present in the death domain within TNFR1 results in apoptosis.[23] TNFα plays an important role in inflammatory disorders such as Psoriasis — consequently a number of TNFα inhibitors are now being used for the treatment of Psoriasis, particularly Psoriatic arthritis.[25]

Yc Chain Family (IL-2, IL-15, IL-4, IL-13)

IL-2 is produced by activated Th1 cells. The target receptors are IL2RA, IL2RB, and IL2RG, which are mainly found in lymphoid tissue. IL-2 acts on activated T and B cells, NK cells, and macrophages to stimulate growth and differentiation of T cells and activation of NK cells. It plays an important role in controlling auto-reactive T cells, while IL-15 promotes effector function of antigen-specific T cells.[26] IL-15 is also produced by activated Th1 cells and can activate NK cells. It can also activate NK cells and stimulate the growth and differentiation of T cells.[2] IL-4 is structurally 30% similar to IL-13, although it has different biological activities. Along with IL-13 it is produced by activated Th2 cells. IL-4 is also produced alone by activated NK cells, mast cells, and basophils. There are two types of receptors for IL-4. The specific receptor for IL-4 found on T cells and NK cells is known as IL-4Rα (CD124) and transmits signals through JAK1 and JAK 3. Another receptor complex that can bind to either IL-4 or IL-13, comprising of IL-4Rα as well as IL-13Rα1 (CD213a1), is found on keratinocytes and endothelial cells. It transmits signals through JAK1 and JAK2. IL-4 stimulates the proliferation and differentiation of naive T cells into Th2 cells. These Th2 cells produce more IL-4, causing a cascade of Th2 cell proliferation and prolongation of the Th2 response. Due to this action on Th2 cells, both IL-4 and IL-13 play an important role in mediating atopic immunity.[227] IL-5 is produced by activated Th2 cells, mast cells, and eosinophils. The specific target receptor for IL-5 is IL-5Ra. IL-5 acts on B cells resulting in their proliferation and production of IgA, in response to antigenic stimulation. It helps in the production of eosinophil precursors in the bone marrow. In response to parasitic infections, IL-5 along with Eotaxin (a chemokine) mobilizes the recruitment of eosinophils from blood and their accumulation in the specific tissue.[28] IL-6 is produced by keratinocytes, fibroblasts, vascular endothelial cells and infiltrating leucocytes, Th2 cells and B cells. IL-6 type cytokines include IL-6, IL-11, LIF (leukemia inhibitory factor), OSM (oncostatin M), ciliary neurotrophic factor, cardiotrophin-1 and cardiotrophin-like cytokines. There are two target receptors for IL-6 - IL-6RA and IL-6RB. It uses the gp130 molecule for signaling by two pathways — the JAK / STAT and the Ras / MAP kinase pathway. It is a pleiotropic cytokine with multiple effects — it stimulates the proliferation of keratinocytes, causes activated B cells to differentiate into plasma cells (which are in turn stimulated to secrete antibodies), induces the differentiation of hematopoietic cells such as myeloid cells, promotes maturation of megakaryocytes, has mitogenic effects on B lineage cells, and mediates systemic acute phase reaction.[29]

Interleukin 10 Family (IL-10, IL-19, IL-22, IL-26, IL-24, IL-20)

IL-10 is produced primarily by Th2 cells. In the skin it is produced by keratinocytes — this production is increased after activation by stimuli such as the UV rays. It is also produced by mast cells, macrophages, and a subset of B cells. The receptors for IL-10 are IL-10RA and IL-10RB, and they are homologous to the receptors for IFNα / β and IFNγ. These receptors use the JAK / STAT pathway. IL-10 is regarded as an anti-inflammatory cytokine, because it acts on antigen-presenting cells such as monocytes, macrophages, and dendritic cells, causing a decrease in production of cytokines such as IL-1, IL-6, and IL-12. It also acts on Th1 cells to inhibit production of Th1 cytokines such as IL-2, TNF-β, and TNF-γ. It stimulates B cells and causes activation of Th2 cells.[30] IL-19, IL-22, and IL-26, are produced by activated T cells and IL-24 is produced by activated monocytes and T-cells. IL-19, IL-20, and IL-24 share common receptors — IL20Rα and IL-20Rβ — these are found on keratinocytes, endothelial cells, and monocytes only in inflammatory conditions such as Psoriasis.[31] IL-20, although structurally related to IL-10 is pro-inflammatory. It is produced by keratinocytes and regulates their role in inflammation.[32]

Interleukin 12 Family (IL-12, IL-23, IL-27)

IL-12 is a pro-inflammatory cytokine that is naturally produced by antigen presenting cells such as dendritic cells, macrophages, monocytes, and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation by bacteria, GM-CSF, and IFNγ. In the skin it is also produced by activated keratinocytes. IL-12 binds to the IL-12 receptor, which is a heterodimeric receptor formed by IL-12R-β1 and IL-12R-β2. The signaling component of IL-12 is the β2 chain, which is expressed in Th1 cells and plays an important role in the production of Type 1 cytokines by Th1 cells. IL-12 plays an important role in the differentiation of naive T cells into Th1 cells and stimulates the growth and function of T cells — hence, it is known as the T cell stimulating factor. It initiates and maintains the Th1 response. It stimulates the production of IFNγ and TNF-α from the T cells and reduces IL-4 mediated suppression of IFN-γ.[33] IL-23 has overlapping activities with IL-12. It is involved in the induction of the T cells producing IL-17. It induces the proliferation of memory T cells, and plays an important role in the inflammatory response against infection.[34] IL-27 is produced by antigen-presenting cells and regulates the activity of B and T lymphocytes.[35]

Interleukin 17 Receptor Family (IL-17,IL-32)

IL-17: The CD4+ T cells designated as Th17 cells are distinctly different from Th1 and Th2 cells and produce IL-17 (also known as IL-17A) and IL-17F. In recent times, it has been shown that IL-17A and IL-17F can also be produced by other cells such as NKT cells and CD8+ cells. IL-17 has pleiotropic effects on tissue cells and immune cells. Hence, it is an important mediator in tissue inflammation. It mobilizes neutrophils, induces the production of various cytokines and chemokines, including TNFα, IL-1β, IL-8, IL-6, GROα, monocyte chemoattractant protein-1 (MCP-1), and G-CSF, and induces the expression of ICAM-1 by monocytes, and fibroblasts. IL-17 modulates the cytokine production by keratinocytes and plays an important role in the immunity against various bacteria and fungi. It is involved in the pathogenesis of various inflammatory dermatoses, such as, Psoriasis, Atopic Dermatitis, and Contact Dermatitis.[36] IL-32 (previously termed NK transcript 4), is produced by mitogen-activated lymphocytes, IFNγ activated epithelial cells, and IL-12, IL-18, and IL-32-activated NK cells. It induces the production of TNF-α, IL-1β, IL-6, and 2 C-X-C chemokine family members involved in several autoimmune diseases. It also activates arachidonic acid metabolism in peripheral blood mononuclear cells by stimulating the release of prostaglandins.[37]

Interferons (IFN)

There are three types of interferons[38]: Type 1 Interferons comprising of IFNα produced by virus-infected leucocytes, IFNβ produced by virus-infected epithelial cells, and virus-infected fibroblasts. A few additional members recently described include IFNε, IFNκ, and IFNω. Both IFNα and IFNβ signal through the two-chain IFNα / β receptor.[39] Type I interferons (IFNs) are expressed as a first line of defense against viral infection.[40] They limit the viral spread during the initial stages of a viral infection, thus facilitating generation of a strong adaptive immune response against the infection. Type I IFNs combat viral infection directly by Inhibing viral replication in infected cells and also indirectly by stimulating the adaptive immune system. They also cause increased expression of MHN Class I molecules, stimulation of NK cell activity, and inhibition of proliferation of various cells.[41] Type I interferons also play an important role in some bacterial and protozoal infections.[42]

Type II Interferons comprise of IFNγ, produced by activated Th1 CD4 T cells, CD8 T cells, and NK cells. The IFNγ, signal through a two-chain receptor specific for IFNγ. IFN-γ displays some of the antiviral properties of type I IFN, but the dominating biological role of IFN-γ seems to be the stimulation of the adaptive immune system by primarily activating T cells. They also have an antiproliferative activity against some cells.[43]

Type III interferons comprise of IFN-λ1 or IL-28A, IFNλ2 or IL-28B, and IFN- λ3 or IL-29. Type III functionally resembles Type I IFN in inducing anti-viral protection. However, it is less potent than the Type I IFN. Type III cytokines have a shared receptor that consists of the β chain of the IL-10 receptor and the α chain of the IL-28 receptor.[44]

Transforming Growth Factor-β (TGF-β) Superfamily

Transforming growth factor (TGF) is a term used to describe two classes of polypeptide growth factors, TGFα and TGFβ. TGFα is produced by kertinocytes and macrophages and induces epithelial development.[45]

TGF-β is a protein that exists in three isoforms called, TGF-β1, TGF-β2, and TGF-β3. TGFβ1 was the initial molecule that was isolated from virally transformed tumor cells. The TGFβ family is part of a superfamily of 30 molecules — the other members of this family include inhibins, activin, anti-müllerian hormone, bone morphogenetic protein, decapentaplegic, and growth / differentiation factors. TGFβ exerts its effects through Type I and Type II cell surface receptors with serine / threonine kinase activity. TGFβ influences various immune and inflammatory processes. It promotes wound healing by inducing fibroblasts to increase the production of collagen, Inhibing production of metalloproteinases by fibroblasts, and stimulating the production of tissue inhibitors of metalloproteinases.[46]

Chemokines (Chemoattractant or Chemotactic cytokines)

Chemokines are a superfamily of about 50, mostly small, chemotactic cytokines that function in leukocyte trafficking, recruitment, and activation. They also play a critical role in many normal and pathophysiological processes such as allergic responses, infectious and autoimmune diseases, angiogenesis, inflammation, tumor growth and metastasis, and hematopoietic development. Each chemokine has 65 – 120 amino acids and a molecular weight of 8 to 11 kD.[47] They are produced by a wide variety of cell types including keratinocytes, NK cells, dendritic cells, mast cells, and so on. The production of chemokines is induced by exogenous irritants and endogenous mediators such as IL-1, TNF-α, PDGF, and IFN-γ.[4849] Chemokines possess conserved amino acids that are important for creating their three-dimensional or tertiary structure, such as (in most cases), four cysteines that interact with each other in pairs. Intramolecular disulfide bonds typically join the first to third, and the second to fourth cysteine residues.[50] Members of the chemokine family are categorized into four groups depending on the structure spacing of their first two cysteine residues (Cys residue) at N terminus.[51]

CXC chemokines

They have a pair of Cys separated by a single residue. 17 CXC chemokines have been described and designated as CXCL1 through 17. The most prominent members of this class are interleukin-8 (IL-8), stromal derived factor-1 (SDF-1), g-interferon inducible protein-10 (IP-10), platelet factor-4 (PF-4), neutrophil activating protein-2 (NAP-2), and melanoma growth stimulating activity (MGSA).[52]

CC chemokines

They have two adjacent Cys near the amino group. Twenty-seven different CC Chemokine ligands (CCL) have been identified and designated as CCL1 through CCL28 (CCL 9 and CCL 10 are identical), Although most members of this group contain four cysteine residues some (CCL1, CCL15, CCL21, CCL23, and CCL28) contain six cysteine residues. The important members of this group are macrophage inflammatory protein-1 (MIP-1a, MIP-1b), regulated upon activation of normal T cell expressed and secreted (RANTES) and monocyte chemoattractant protein-1(MCP-1).[53]

CX3C chemokines

They contains two Cys separated by three residues. The only member of this group is fractalkine / neurotactin.[54]

C chemokines

They contain a single Cys. The two members of this group are XCL1 (lymphotactin α) and XCL2 (lymphotactin β).[55]

Chemokine receptors

The chemokines bind to specific cell surface receptors. There are 19 distinct chemokine receptors, all of which are members of a large protein family of G protein-coupled receptors. Each of them has a seven transmembrane structure and couple to the intracellular heterotrimetric G-protein for signal transduction within a cell. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in the intracellular calcium ions (calcium signaling). This causes cell responses, including chemotaxis. Chemokine receptors are divided into four different families: CXC chemokine receptors, CC chemokine receptors, CX3C chemokine receptors, and XC chemokine receptors, which correspond to the four distinct subfamilies of the chemokines they bind.[56]

Functions

Chemokines trigger a large number of biological responses, including cell polarization, movement, immune and inflammatory responses, and prevention of HIV-1 infection. They use a number of signaling pathways to perform their functions including the JAK / STAT pathway. They are less pleiotropic than the primary proinflammatory cytokines, because they are not potent inducers of other cytokines and exhibit more specialized functions in inflammation and repair. Inflammatory chemokines function mainly as chemoattractants for leukocytes, recruiting monocytes, neutrophils, and other cells from the blood to the sites of infection or tissue damage. Their release is often stimulated by pro-inflammatory cytokines such as IL-1. They perform this function by (a) sending signals to stop the leucocytes from flowing into the blood vessels at the site of inflammation (b) causing transmigration of leucocytes through the vessel wall, and (c) causing migration of leucocytes to sites of inflammation in the epidermis and dermis. Cells that are attracted by chemokines follow a signal of increasing chemokine concentration toward the source of the chemokine. Some chemokines direct lymphocytes to the lymph nodes so that they can screen for invasion of pathogens by interacting with the antigen-presenting cells. These are known as homeostatic chemokines. Some chemokines play important roles in the development, by promoting angiogenesis or guiding cells to tissues that provide specific signals critical for cellular maturation.[57]

Conclusion

The role of cytokines in cutaneous tissues and in various physiological and pathological processes is being continuously enunciated. This has not only helped in the understanding of the etiopathology of various disease processes, but also in developing various biologicals for the treatment of these disorders.