Chemokine

Three-dimensional structure of the chemokine interleukin-8 (CXCL8) in its dimeric form

Chemokines (name derived from chemo tactical cyto kine ) are a group of cytokines , so small signaling proteins that a migration (for cell chemotaxis trigger). The cells move along a concentration gradient to the location of the highest chemokine concentration. Chemokines play a central role in the migration of immune cells in tissue and in their migration from the blood. Some chemokines also have an activating effect on immune cells, and some are involved in organ development and angiogenesis . The approximately 50 different chemokines are produced by immune cells and many tissue cells. They develop their effect after binding to chemokine receptors , which are widespread in the immune system . Without the cell migration triggered by chemokines, the immune system could not function.

Structure and nomenclature

Three-dimensional structure of the chemokines

Chemokines are small proteins that consist of approx. 75–125 amino acids and have a molar mass of 8 to 14 kDa . The amino acid sequence is conserved differently within the chemokine family, the homology can be less than 20% or more than 90%. The spatial folding or tertiary structure, on the other hand, is strictly conserved: the amino terminus is disordered, the main body is formed by a three-stranded antiparallel β-sheet, and the carboxy terminus ends with an α-helix. Another conserved feature of chemokines is a group of cysteine residues that can form one or two disulfide bridges .

The systematic nomenclature of chemokines is derived from the number and position of the cysteine residues at the amino terminus. Four subfamilies can be distinguished: In the CC chemokines the first two cysteines follow one another, in the CXC chemokines they are separated from one another by an amino acid, and in the CX3C chemokines by three amino acids. In these chemokine families, two disulfide bridges are always formed. In contrast, in the C family there is only one conserved cysteine at the amino terminus, and only one disulfide bridge is formed. The systematic names of the individual chemokines are made up of the family name (CC, CXC, CX3C, XC), the letter L for ligand and consecutive numbering. In addition, however, the names that were given to them in the first description are often used.

function

The main function of the chemokines is to induce chemotaxis in immune cells. A distinction can be made between inflammatory (or inducible) and homeostatic (or constitutive) chemokines. Most chemokines are inflammatory cytokines. B. triggered by injury, infection, or inflammation, and their release attracts immune cells. So they act like an alarm signal. The homeostatic chemokines, on the contrary, are continuously produced and are involved in the organization of lymphoid organs and the monitoring of healthy tissues. This group includes CCL18, CCL19, CCL21, CXCL12, CXCL13 and CXCL14. Another group of chemokines cannot be clearly assigned to either category; these are CCL1, CCL17, CCL20, CCL22, CCL25, CXCL9, CXCL10, CXCL11 and CXCL16.

The function of the chemokines is not necessarily linked to forms that are freely soluble in the tissue fluid or swim in the blood. Concentration gradients are also formed by a firm bond to tissue structures. Chemokines have many basic amino acids and are therefore positively charged; this enables a firm bond to negatively charged sugar molecules ( glycosaminoglycans ), which are widespread on the surface of cells and in proteins of the extracellular matrix . Some chemokines such as CCL2, CCL3 and CCL5 lose their function in the body when binding to glycosaminoglycans is no longer possible. However, the exact relationship between binding to tissue structures and function is not yet understood.

Familys

Surname	Genes	Other names)	Uniprot

CC chemokines
CCL1	Scya1	I-309, TCA-3	P22362
CCL2	Scya2	MCP-1	P13500
CCL3	Scya3	MIP-1α	P10147
CCL4	Scya4	MIP-1β	P13236
CCL5	Scya5	RANTES	P13501
CCL6	Scya6	C10, MRP-2	P27784
CCL7	Scya7	MARC, MCP-3	P80098
CCL8	Scya8	MCP-2	P80075
CCL9 / CCL10	Scya9	MRP-2, CCF18, MIP-1γ	P51670
CCL11	Scya11	Eotaxin	P51671
CCL12	Scya12	MCP-5	Q62401
CCL13	Scya13	MCP-4, NCC-1, Ckβ10	Q99616
CCL14	Scya14	HCC-1, MCIF, Ckβ1, NCC-2, CCL	Q16627
CCL15	Scya15	Leukotactin-1, MIP-5, HCC-2, NCC-3	Q16663
CCL16	Scya16	LEC, NCC-4, LMC, Ckβ12	O15467
CCL17	Scya17	TARC, dendrokine, ABCD-2	Q92583
CCL18	Scya18	PARC, DC-CK1, AMAC-1, Ckβ7, MIP-4	P55774
CCL19	Scya19	ELC, Exodus-3, Ckβ11	Q99731
CCL20	Scya20	LARC, Exodus-1, Ckβ4	P78556
CCL21	Scya21	SLC, 6Ckine, Exodus-2, Ckβ9, TCA-4	O00585
CCL22	Scya22	MDC, DC / β-CK	O00626
CCL23	Scya23	MPIF-1, Ckβ8, MIP-3, MPIF-1	P55773
CCL24	Scya24	Eotaxin-2, MPIF-2, Ckβ6	O00175
CCL25	Scya25	TECK, Ckβ15	O15444
CCL26	Scya26	Eotaxin-3, MIP-4α, IMAC, TSC-1	Q9Y258
CCL27	Scya27	CTACK, ILC, Eskine, PESKY, skinkine	Q9Y4X3
CCL28	Scya28	MEC	Q9NRJ3
CXC chemokines
Surname	Genes	Other names)	Uniprot
CXCL1	Scyb1	Gro-α, GRO1, NAP-3	P09341
CXCL2	Scyb2	Gro-β, Gro2, MIP-2α	P19875
CXCL3	Scyb3	Gro-γ, Gro3, MIP-2β	P19876
CXCL4	Scyb4	PF-4	P02776
CXCL5	Scyb5	ENA-78	P42830
CXCL6	Scyb6	GCP-2	P80162
CXCL7	Scyb7	NAP-2, CTAPIII, β-Ta, PEP	P02775
CXCL8	Scyb8	IL-8, NAP-1, MDNCF, GCP-1	P10145
CXCL9	Scyb9	MIG, CRG-10	Q07325
CXCL10	Scyb10	IP-10, CRG-2	P02778
CXCL11	Scyb11	I-TAC, β-R1, IP-9	O14625
CXCL12	Scyb12	SDF-1, PBSF	P48061
CXCL13	Scyb13	BCA-1, BLC	O43927
CXCL14	Scyb14	BRAK, bolekine	O95715
CXCL15	Scyb15	Lungkine, WECHE	Q9WVL7
CXCL16	Scyb16	SRPSOX	Q9H2A7
CXCL17	VCC-1	DMC, VCC-1	Q6UXB2
C chemokines
Surname	Genes	Other names)	Uniprot
XCL1	Scyc1	Lymphotactin α, SCM-1α, ATAC	P47992
XCL2	Scyc2	Lymphotactin β, SCM-1β	Q9UBD3
CX3C chemokines
Surname	Genes	Other name (s)	Uniprot
CX3CL1	Scyd1	Fractalkine, Neurotactin, ABCD-3	P78423

CC family

In humans, this family has 24 members, and they prefer to act on monocytes, lymphocytes, eosinophils and basophils.

CXC family

The total of 16 known CXC chemokines in humans can be subdivided by the absence or presence of other structural features, such as the ELR motif, which consists of three amino acids. ELR-positive CXC chemokines are considered to be potent promoters of angiogenesis , while ELR-negative CXC chemokines mostly have an antiangiogenic effect. The receptors for these chemokines are often found on neutrophils.

CX3C family

The chemokine "Fractalkin", cloned in 1997, is the only member of this family. Fractalkin is characterized by a CX3C motif and the expression of the chemokine domain via a mucin-like, membrane-anchored protein strand. The gene that codes for the CX3C chemokine is located on chromosome 16 . Fractalkin is expressed in the membrane on activated endothelial cells and can be secreted into the environment. So they occur as membrane-bound or soluble molecules. Fractalkines act on T lymphocytes and monocytes . Soluble fractalkines regulate leukocyte migration . The membrane-like shape mediates an increased adherence of the T-cells and monocytes. Thus, fractalkines are able to act directly on the step of leukocyte extravasation, in which the cell is transferred from rolling on the endothelium into a firm adhesion, which is followed by the subsequent leukodiapedesis in the tissue. In addition, the expression of the fractalkine in the brain has been observed. It is found on activated microglial cells , which suggests that it plays a role in inflammatory processes in the central nervous system . Moreover, the chemotaxis and activation of neutrophil granulocytes affected the brains of Fraktalkinen.

C family

XCL1 (also Lymphotactin or ATAC) is released mainly by activated CD8 T cells and by NK cells . In humans there is a second gene (XCL2) that is identical to XCL1 except for two amino acids.

literature

Charles A. Janeway, Paul Travers, Mark Walport: Immunobiology . B&T; 6th edition (2005), ISBN 0-8153-4101-6
SJ Allen et al .: Chemokine: receptor structure, interactions, and antagonism. In: Annu. Rev. Immunol. Vol. 25, 2007, pp. 787-820. PMID 17291188 .

Individual evidence

↑ EJ Fernandez et al .: Structure, function, and inhibition of chemokines. In: Annu. Rev. Pharmacol. Toxicol. Vol. 42, 2002, pp. 469-499. PMID 11807180 .
^ A. Zlotnik et al .: Chemokines: a new classification system and their role in immunity. In: Immunity . Vol. 12, No. 2, 2000, pp. 121-127. PMID 10714678 .
↑ Strieter RM, Polverini PJ, Kunkel SL, et al. : The functional role of the ELR motif in CXC chemokine-mediated angiogenesis . In: J. Biol. Chem. . 270, No. 45, November 1995, pp. 27348-57. PMID 7592998 .
↑ JF Bazan, KB Bacon et al.: A new class of membrane-bound chemokine with a CX3C motif. In: Nature . Volume 385, Number 6617, February 1997, pp. 640-644, ISSN 0028-0836 . doi : 10.1038 / 385640a0 . PMID 9024663 .
↑ Y. Pan, C. Lloyd et al: Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. In: Nature. Volume 387, Number 6633, June 1997, pp. 611-617, ISSN 0028-0836 . doi : 10.1038 / 42491 . PMID 9177350 .

[1] EJ Fernandez et al .: Structure, function, and inhibition of chemokines. In: Annu. Rev. Pharmacol. Toxicol. Vol. 42, 2002, pp. 469-499. PMID 11807180 .

[2] A. Zlotnik et al .: Chemokines: a new classification system and their role in immunity. In: Immunity . Vol. 12, No. 2, 2000, pp. 121-127. PMID 10714678 .

[pmid7592998-3] Strieter RM, Polverini PJ, Kunkel SL, et al. : The functional role of the ELR motif in CXC chemokine-mediated angiogenesis . In: J. Biol. Chem. . 270, No. 45, November 1995, pp. 27348-57. PMID 7592998 .

[PMID9024663-4] JF Bazan, KB Bacon et al.: A new class of membrane-bound chemokine with a CX3C motif. In: Nature . Volume 385, Number 6617, February 1997, pp. 640-644, ISSN 0028-0836 . doi : 10.1038 / 385640a0 . PMID 9024663 .

[PMID9177350-5] Y. Pan, C. Lloyd et al: Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. In: Nature. Volume 387, Number 6633, June 1997, pp. 611-617, ISSN 0028-0836 . doi : 10.1038 / 42491 . PMID 9177350 .