Chemokines

Chemokines, a subgroup of cytokines, are small (size between 8 and 10 kDa), chemotactically active proteins (signal proteins). They are common in all vertebrates, some virus types and bacteria. In humans, about 50 chemokines are currently known. A strongly conserved structural feature of all chemokines is a fixed group of cysteine residues that is stabilized by 1 or 2 disulfide bridges. This key structural position in the molecule is responsible for its fixed 3-dimensional structure (see below chemokines).

In the CC-chemokines the cysteines follow each other directly (see figure), in the CXC-chemokines they are separated by 1, in the CXXXC-chemokines by 3 other amino acids. Chemokines are produced and secreted by a large number of immune cells. They mediate their signals by means of specific chemokine receptors via G-proteins. Some chemokines have a pro-inflammatory effect, others have a regulatory effect on the development and homeostasis of tissues.

Increased chemokine expressions are found in chronic inflammatory diseases such as HIV infection, atopic eczema, bronchial asthma, allergic rhinitis and psoriasis vulgaris. Chemokines play a positive role, e.g. in wound healing, haematopoiesis (blood formation) or the defence against infections. The fact that chemokine receptors are not only present on inflammatory cells but also on tumor cells and endothelial cells suggests that they are also involved in the migration of tumor cells or the metastatic behavior of the various tumors.

The following subfamilies were classified:

• CC chemokines (or β chemokines): They contain two directly adjacent amino-terminal cysteine residues.
• CXC chemokines (or α chemokines): They contain C1 and C2 separated by a single amino acid.
• CX3C chemokines: Contain C1 and C2 separated by three amino acids.
• C-chemokines: Contain only the first and third cysteine residues (C1 and C3).
• The 5th family of chemokines is encoded by viral genes.

CC Chemokines: The CC chemokine family consists of 28 members in humans. They act mainly on immune cells such as monocytes, lymphocytes, eosinophil and basophil granulocytes.

• CCL1 (TCA-3)
• CCL2 (MCP-1)
• CCL3 (MIP-1alpha)
• CCL4 (MIP-1beta)
• CCL5 (RANTES)
• CCL6 (C10, MRP-2)
• CCL7 (MARC, MCP-3)
• CCL8 (MCP-2
• CCL9/CCL10 (MRP-2, CCF18, MIP-1gamma)
• CCL10 (identical with CCL9)
• CCL11 (Eotaxin-1)
• CCL12 (MCP-5)
• CCL13 (MCP-4, NCC-1, Ckβ10)
• CCL14 (HCC-1, MCIF, Ckβ1, NCC-2, CCL)
• CCL15 (Leukotactin-1, MIP-5, HCC-2, NCC-3)
• CCL16 (LEC, NCC-4, LMC, Ckβ12)
• CCL17 (TARC, dendrokine, ABCD-2)
• CCL18 (PARC, DC-CK1, AMAC-1, Ckβ7, MIP-4)
• CCL19 (ELC, Exodus-3, Ckβ11)
• CCL20 (LARC, Exodus-1, Ckβ4)
• CCL21 (SLC, 6Ckine, Exodus-2, Ckβ9, TCA-4)
• CCL22 (MDC, DC/β-CK)
• CCL23 (MPIF-1, Ckβ8, MIP-3, MPIF-1)
• CCL24 (Eotaxin-2, MPIF-2, Ckβ6)
• CCL25 (TECK, Ckβ15)
• CCL26 (Eotaxin-3, MIP-4α, IMAC, TSC-1)
• CCL27 (CTACK, ILC, Eskine, PESKY, skinkine)
• CCL28 (MEC)

CXC chemokines: Currently, 16 CXC chemokines are known to be present in humans. CXC chemokines are divided by further structural features (e.g. the ELR motif consisting of 3 amino acids): ELR-positive CXC chemokines are promoters of angiogenesis, ELR-negative CXC chemokines have an anti-angiogenetic effect. The receptors for these chemokines are often found on neutrophil granulocytes.

• CXCL1 (Gro-α, GRO1, NAP-3)
• CXCL2 (Gro-β, GRO2, MIP-2α)
• CXCL3 (Gro-γ, GRO3, MIP-2β)
• CXCL4 (PF-4)
• CXCL5 (ENA-78)
• CXCL6 (GCP-2)
• CXCL7 (NAP-2, CTAPIII, β-Ta, PEP)
• CXCL8 (IL-8, NAP-1, MDNCF, GCP-1)
• CXCL9 (MIG, CRG-10)
• CXCL10 (IP-10, CRG-2)
• CXCL11 (I-TAC, β-R1, IP-9)
• CXCL12 (SDF-1, PBSF)
• CXCL13 (BCA-1, BLC)
• CXCL14 (BRAK, bolekine)
• CXCL15 (Lungkine, WECHE)
• CXCL16 (SRPSOX)
• CXCL17 (DMC, VCC-1)

C Chemokines: XCL1 (also known as lymphotactin or ATAC) is mainly released by activated CD8 T cells and by NK cells. In humans there is a second chemokine (XCL2) which is identical to XCL1 except for two amino acids, but is regulated independently.

• XCL1( lymphotactin α, SCM-1α, ATAC)
• XCL2 (lymphotactin β, SCM-1β)

CX3C chemokines: The chemokine "fractalkin" is the only member of this family. Characteristic for fractalkin is the CX3C motif and the expression of the chemokine domain. Fractalkin is expressed on activated endothelial cells in the membrane. The chemokine acts on T lymphocytes and monocytes. Soluble fractalkines regulate leukocyte migration.

• CX3CL1 (Fractalkines, Neurotactin, ABCD-3)

Chemokines can also be divided into 2 groups according to their function:

Homeostatic chemokines: these are mainly produced in the thymus and other lymphatic tissues. They are responsible for the basal leukocyte migration. The following chemokines belong to this group: CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13. Protoypes of this chemokine group are the chemokines CCL19 and CCL21 (produced in lymph nodes and by lymphatic endothelial cells) and their receptor "CCR7".

Inflammatory chemokines are secreted in high concentrations in pathological (infectious or toxic - e.g. urate crystals) processes under the influence of various cytokines such as Interleukin-1, TNF-alpha or by microbial products. They serve as attractors of immune cells to the site of inflammation. To this group of proinflammatory chemokines belong: CXCL-8, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL10. An important representative of this group is CXCL-8, a chemokine that attracts neutrophil granulocytes.

Almost all chemokines contain four conserved cysteine amino acid residues (C1-C4). The nomenclature for chemokines is not yet uniform. One part is named according to its specific function (e.g. MCP-1 = monocyte chemotactic protein 1), another according to its cellular source (e.g. RANTES = regulated upon activation, normal T-expressed and secreted = CCL5) or arbitrarily like interleukin-8.

Monocytes / Macrophages: The key chemokines that attract these cells are CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL17 and CCL22; the chemokines CCL19, CCL21, CCL24, CCL25, CXCL8, CXCL10, and XCL2 induce specific M1 macrophage chemotaxis, while CCL7 exerts chemotaxis on both M1 and M2 macrophages.

T lymphocytes: 4 key chemokines are responsible for the directed migration of T lymphocytes: CCL2, CCL1, CCL22 and CCL17.

Mast cells express various chemokine receptors on their surface: CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, and CXCR4. Known ligands of these receptors are the chemokines CCL2, CCL5.

Eosinophilic granulocytes: The decisive chemokines (especially CC-chemokines) responsible for the migration of these cells are: CCL11, CCL5, CCL7, CCL13, CCL24, CCL26 and CCL3. CCL11 and CCL5 (RANTES) act on eosinophil granulocytes via the specific receptor CCR3.

Neutrophil granulocytes: An important chemokine (especially CXC chemokines) responsible for the migration of these cells is CXCL8 (IL-8).

One member of the CC chemokine family, CCL13, regulates the migration of monocytes, macrophages, T cells and eosinophilic granulocytes via their CCR2 and CCR3 chemokine receptors. CCL13 is increasingly expressed in the skin of patients with systemic scleroderma. The serum level of this chemokine (diagnostic marker) is also elevated.

1. Homey B et al (2006) Cytokines and chemokines orchestrate atopic skin inflammation. J Allergy Clin Immunol 118: 179-189
2. Vielhauer V et al (2007) Chemokines and chemokine receptors as therapeutic targets in lupus nephritis. Semin Nephrol 27: 81-97