Chemotactic factor

Small cytokines or signal proteins secreted by cells

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Chemokines: a class of chemokines Cell secretion Small of cell factor or Signal protein 。 Because they have the ability to induce directional chemotaxis of nearby reaction cells, they are named Chemokine 。

Chinese name: Chemotactic factor
Foreign name: chemokines
Alias: Chemotactic hormone

molecular weight: 8-10 kDa
Features: Directed chemotaxis
Nature: protein

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▪ Classification of action cells
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brief introduction

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Chemotactic factor

The human body is defending and clearing the invasion pathogen When waiting for foreign matters Immune cell Some substances can cause the function of directional chemotaxis, which is called chemotactic agent or chemokine, also called chemotactic hormone, chemokine or chemical hormone. Chemokine is one Small molecule cell factor Family proteins, these small proteins have Directional cell Chemotaxis It gets its name. Some of these proteins have other names in the history, including SIS cytokine family, SIG cytokine family, SYC cytokine family and Platelet factor -4 Families.

The common structural features of chemokine proteins include low molecular weight (about 8-10 kDa) and four conserved positions Cysteine Residue To ensure that Tertiary structure 。

Some chemokines are considered to be Proinflammatory cytokines , can be immune response In process induction immune system % of the cells entered the infection site. Some chemokines are believed to maintain the body Self-regulation It controls cell migration during normal tissue maintenance or development. At all vertebrate Some viruses and some bacteria have chemokines, but others invertebrate Not found in.

Chemokines are divided into four main categories Subfamily : CXC, CC, CX3C, and XC. All these proteins pass through G protein Connected span Membrane receptor (called chemokine receptors) interact to exert their biological effects protein Combine to Chemokine receptor The chemokine receptor is a transmembrane receptor coupled with G protein and selectively expressed in Target cell Surface.

structure characteristics

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Chemokines have four conserved cysteine residues to ensure their tertiary structure

All chemokines are small, with molecular weights between 8 and 10 kDa. About 20-50% of them are the same; In other words, they have the same gene sequence and amino acid Sequence homology 。 They also have conservative amino acids, which are important for forming their three-dimensional or tertiary structure, such as four Cysteine Interaction forms a Greek key shape, which is a characteristic of chemokines. Intramolecular disulfide bonds usually connect the first to the third cysteine residues, and the second to the fourth cysteine residues, which are numbered when they appear in the protein sequence of chemokines. Typical chemokine proteins are produced in the form of peptide precursors Cell secretion In the process of signal peptide 。 Among chemokines, the first two cysteine are close to the n-terminal of mature protein, the third cysteine is located at the molecular center, and the fourth cysteine is close to the C-terminal. After the first two cysteine, there is a ring of about 10 amino acids, called N ring.

function

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The main function of chemokines is to induce directional migration of cells, and the cells attracted by chemokines follow the chemokines Concentration increase The migration of the signal of. Some chemokines Immune surveillance In process control Immune cell Chemotaxis, such as induction lymphocyte reach lymph gland The chemokines in these lymph nodes interact with Antigen presenting cells Interact to monitor the invasion of pathogens. These are called steady-state chemokines, which are produced and secreted without stimulating the source cells. Some chemokines play a role in development; They can stimulate the formation of new blood vessels（ Angiogenesis ）； It guides cells into tissues and provides specific signals for cell maturation. Other chemokines inflammatory reaction Plays a key role in coping with bacterial infection viral infection It is released by a variety of cells; It can also be caused by non Infectivity The stimulation of silicon dioxide Inhalation, Urolithiasis And so on. The release of chemokines is usually determined by Inflammatory cytokines as Interleukin 1 ( IL -1) Stimulation. Inflammatory chemokines are mainly used as white blood cell Chemokine of, attracted from the blood monocyte 、 Neutrophils And others Effector cell To infection or tissue damage Part of. Some inflammatory chemokines can activate cells to start immune reaction Or promote wound healing 。 They are released by many different cell types and immune system And the cells of adaptive immune system play a guiding role.

The main function of chemokines is in inflammation and the body Equilibrium process Managing the migration of white blood cells to their respective locations（ homing )。

Basic homing effect: in thymus and lymphoid tissue Basic steady-state chemokines produced in. Chemokines CCL19 and CCL21 (in lymph nodes and lymph gland endothelial cells And its receptor CCR7 (expressed in cells destined to homing to these organs) are the best examples of their homeostatic function in homing. Take advantage of these ligand Can make Antigen-presenting cell (APC) in Adaptive immune response Metastasis to lymph nodes in the process. Other steady-state chemokine receptors include CCR9, CCR10 and CXCR5 As part of the cell address for Tissue specificity The homing of white blood cells is very important. CCR9 supports leukocyte migration to the intestine, CCR10 supports skin migration, and CXCR5 supports b cell migration to lymph nodes Follicles Migration. CXCL12 (SDF-1) generated in bone marrow promotes bone marrow Microenvironment Medium B Progenitor cell Proliferation of

Inflammatory homing: Inflammatory chemokines produce high concentrations in the process of infection or injury, and determine the migration of inflammatory leukocytes to the damaged area. Typical inflammatory chemokines include CCL2, CCL3 and CCL5, CXCL1, CXCL2 and CXCL8. A typical example is CXCL-8, which is Neutrophils Chemotactic agent. Compared with the steady-state chemokine receptor, the binding receptor and inflammatory chemokine were significantly mixed. This often makes the receptor Specificity The study of treatment is complicated.

type

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Structure classification

Chemotactic cytokine According to its amino End（ N-end ） Cysteine It can be divided into four sub families: CXC, CC, XC and CX3C

CC chemokine subfamily ：CCL1、 CCL2、CCL3、CCL4、CCL5、CCL6、CCL7、CCL8、CCL9、CCL10、CCL11、CCL12、CCL13、CCL14、CCL15、CCL16、CCL17、CCL18、CCL19、CCL20、CCL21、CCL22、CCL23、CCL24、CCL25、CCL26、CCL27、CCL28

CXC chemokine subfamily ：CXCL1、 CXCL2、CXCL3、CXCL4、CXCL5、CXCL6、CXCL7、CXCL8、CXCL9、CXCL10、CXCL11、CXCL12、CXCL13、CXCL14、CXCL15、CXCL16、CXCL17

XC chemokine subfamily ：XCL1、XCL2

CX3C chemokine subfamily ：CX3CL1

Function classification

Chemokines can be divided into two categories according to their different functions:

Homeostasis Chemokines: generated in some organizations, responsible for basic white blood cell Migration. Including: CCL14, CCL19, CCL20, CCL21, CCL25, CCL27, CXCL12 and CXCL13. (This classification is not strict, for example, CCL20 can also be used as an inflammatory chemokine)

Proinflammatory chemokine : Formed under pathological conditions (under proinflammatory stimulation, such as IL -1、 TNF -α、 LPS or Viruses ）And actively participate inflammatory reaction , attract Immune cell To the inflamed area. For example: CXCL-8 CCL2、CCL3、CCL4、CCL5、CCL11、CXCL10。

Classification of action cells

Chemokines can be divided into the following categories according to the cell types of their chemotaxis:

Single core/ macrophage Chemotactic factor The key chemokines that attract monocytes/macrophages to inflammatory sites include: CCL2, CCL3, CCL5, CCL7, CCL8, CCL13, CCL17, and CCL22.

T lymphocyte chemotactic factor : Participation T lymphocytes The four key chemokines recruited to inflammatory sites are CCL2, CCL1, CCL22 and CCL17. In addition, activated T cells induce CXCR3 expression, and activated T cells are attracted by the inflammatory site and secreted at the inflammatory site IFN-γ Induced chemokines CXCL9, CXCL10 and CXCL11.

Mast cell chemotactic factor : Surface expression of multiple chemokine receptors: CCR1 CCR2、CCR3、CCR4、 CCR5 、CXCR2、 CXCR4 。 The ligands of these receptors CCL2 and CCL5 are in the lung mast cells It plays an important role in recruitment and activation. There is also evidence that CXCL8 may inhibit mast cells.

Eosinophil chemotactic factor ： Eosinophils Migration to various organizations involves several chemokines of CC family: CCL11, CCL24, CCL26, CCL5, CCL7, CCL13 and CCL3. Chemokines CCL11 (eotaxin) and CCL5 (rantes) play a role through a specific receptor CCR3 on the surface of eosinophils, and eosinophils play an important role in the initial recruitment to lesions.

Neutrophil chemotactic factor : Mainly regulated by CXC chemokines. For example, CXCL8 (IL-8) is Neutrophils And activate its metabolism and Degranulation 。

recipient

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Chemokine receptor is found on the surface of white blood cells and contains 7 transmembranes Domain Of G protein coupled receptor 。 So far, about 19 different chemokine receptors have been identified. According to the type of chemokine they bind, they are divided into four families: CXCR bound with CXC chemokine, CCR bound with CC chemokine, CX3CR1 bound with CX3C chemokine (CX3CL1), and XCR1 bound with two XC chemokine (XCL1 and XCL2). They have many common structural features: they are similar in size (about 350 amino acid ）, there is a short acidity N-end , 7 helical transmembrane domains, 3 intracellular and 3 extracellular hydrophilic rings, and one cell containing Receptor regulation important serine and threonine Residue C-end 。 The first two cells Outer ring And each has a conservative Cysteine Residues, allowing the formation of a Disulfide bond Between these rings. G protein coupling To the C-terminal of chemokine receptor to activate the receptor signal transduction , and the N-terminal domain of chemokine receptor determines Ligand binding Of Specificity 。

signal transduction

Chemokine receptor binds to G protein Transfer cell Signal. G protein is activated by chemokine receptor, resulting in the following Phospholipase C ( PLC ）Enzyme activation. PLC calls one Phosphatidylinositol The molecule of (4,5) - diphosphate (PIP2) splits into two Second Messenger Molecules, called Inositol triphosphate ( IP3 ）And Diacylglycerol ( DAG ）To trigger Intracellular signal event; DAG activation is another method called Protein kinase C (PKC), while IP3 triggers the release of intracellular calcium. These events promoted many signaling cascade (such as MAP kinase pathway), produce chemotaxis Degranulation , Release superoxide anion And intracellular chemokine receptors Adhesive molecule (called integrin ）Activity change of.

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