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Chemokines

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Chemokines

  1. 1. Presented by: Shruti sharma, Pharmacology, 2nd semester.
  2. 2.  Chemokines are small heparin-binding proteins that direct the movement of circulating leucocytes to the site of inflammation and injury.  Chemokines are 8-10 kD proteins with 20-70 % homology in amino acid sequence.  Chemokines act like chemoattractant cytokine.
  3. 3. Chemokine Function
  4. 4.  Proteins are classified into the chemokine family based on their structural characteristics, not just their ability to attract cells.  They possess conserved amino acids that are important for creating their 3- dimensional or tertiary structure, such as (in most cases) four cysteines that interact with each other.
  5. 5. Most chemokines have 4 cysteine residues which form disulphide bonds: 1. CC class – The first two cysteines are adjacent (example: MCP-1, RANTES) 2. CXC class- The first two cysteines are not adjacent (example: IL-8) 3. C class – Only has 2 cysteines not 4 (example: Lymphotactin) 4. CX3C class – Has 3 amino acids between the first two cysteines and a different N- terminal
  6. 6. Classification of chemokines
  7. 7. Chemokine Receptors  Chemokine receptors are defined by function, not structure:- they bind chemokines and transduce signal.  To date all known chemokine receptors are members of the 7TM GPCR superfamily, coupling to Gi.
  8. 8. CXC chemokines- The two N-terminal cysteines of CXC chemokines (or α- chemokines) are separated by one amino acid, represented in this name with an "X”. CXC chemokines Glutamic acid leucine Glutamic acid leucine arginine positive arginine negative (ELR- Motif) (ELR without Motif) Eg. IL-8 Eg. IL-8, GCP2, GROα,β,Ƴ, MCP1-5, RANTES.
  9. 9. ELR +ve : means that induce the migration of neutrophils and interact with CXCR1 and CXCR2 chemokine receptors. eg. IL-8 which induces neutrophils to leave the bloodstream and enter into the surrounding tissue. ELR –ve : means that induce migration of lymphocytes and interact with CXCR1 to CXCR7 chemokine receptors. eg. IL-8, GCP2, GRO-α,β,Ƴ, MCP1-5 $ RANTES, MCP( monocyte chemoattractant proteins) RANTES (regulated upon activation , normal T-cell expressed and regulated).
  10. 10. CC Chemokine  Having ability to induce migration of monocytes, NK cells, dendritic cells.  Eg. MCP- Monocyte chemoattractant protein (MCP)-1 (CCL2) specifically attracts monocytes and memory T cells.  Other example is RANTES- c-c motif ligand 5 (i.e. CCL5) is a protein which in humans is encoded by the CCL5 gene known as RANTES. That attracts cells such as T-cells, basophils, & eosinophils, that express the receptor CCR5.
  11. 11. CXXXC chemokines-  in which 3 amino acid residue is present between two cysteines residues.  Its also known as α chemokines  It work as both- Chemoattractant Adhesion molecule Eg. fractalkine
  12. 12. C chemokines (or γ chemokines)  Unlike all other chemokines in that it has only two cysteines; one N-terminal cysteine and one cysteine downstream.  Two chemokines have been described for this subgroup and are called: 1. XCL1 (lymphotactin-α) and 2. XCL2 (lymphotactin-β).
  13. 13. GDP+ G-protein subunit G-protein become inactive binding of the chemokine ligand, chemokine receptors associate with G-proteins then GDP GTP and the dissociation of the different G protein subunits. The subunit called Gβ activates an enzyme known as PLC Now, PLC cleaves PIP2 to form two second messenger molecules called IP3 and DAG DAG activates another enzyme called PKC, and IP3 triggers the release of calcium from intracellular stores. Eg. IL8 binds to receptors CXCR1 &CXCR2, a rise of calcium they activate PLD and that initiate intracellular signalling cascade called MAP kinase pathway
  14. 14. Extravasation and chemokines/receptors
  15. 15. Regulation of integrines by chemokines
  16. 16. 1. Cancer 2. Asthma and allergy 3. Autoimmunity 4. Transplantation 5. HIV 6. Inflammatory diseases such as - rheumatoid arthritis - osteoarthritis - atherosclerosis - psoriasis and - inflammatory bowel disease
  17. 17.  Schematic representation of the proposed mechanism of lymphocyte recruitment by CXCR3-binding chemokines in endocrine autoimmunity. Thyroid follicular cells secrete CXCL9, CXCL10, and CXCL11 upon stimulation with IFN-γ and TNF-α. Chemokines, in turn, drive chemotaxis from blood vessels of T cells expressing the chemokine receptor CXCR3.  This particular subset of T cells shows a prevalent Th1 immune phenotype and produces IFN-γ, thus perpetuating the inflammatory process.  This loop of events supports the active role played by thyroid follicular cells and in general by cells of the glandular epithelium (a similar mechanism has been demonstrated for β-cells and adrenal cells of the zona fasciculata) in determining the specificity of the infiltrating lymphocytes and in maintaining the autoimmune process.
  18. 18.  Chronic rejection of allografts is mediated by a tandem of alloantigen-dependent and -independent factors. The oxidative stress inherent to the transplantation procedure operates within a milieu of immunologic factors that contribute to the later development of chronic rejection.  The aim of this study is investigate the role that early myocardial oxidative stress signaling pathways may have in the development of GCAD using rodent heart transplant models.  Our working hypothesis is that myocardial oxidative stress following cardiac transplantation contributes to the development of GCAD via a bcl-2-associated mechanism.
  19. 19.  Intramolecular disulfide bonds typically join the first to third, and the second to fourth cysteine residues, numbered as they appear in the protein sequence of the chemokine.  The first two cysteines, in a chemokine, are situated close together near the N-terminal end of the mature protein, with the third cysteine residing in the centre of the molecule and the fourth close to the C-terminal end.  A loop of approximately ten amino acids follows the first two cysteines and is known as the N-loop.  This is followed by a single-turn helix, called three β- strands and a C-terminal α-helix. These helices and strands are connected by turns called 30s, 40s and50s loops; the third and fourth cysteines are located in the 30s and 50s loops.

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