Chemokines

1. Presented by:
Shrutisharma,
Pharmacology,
2
nd
semester.

2. Chemokinesaresmallheparin-bindingproteinsthatdirect
themovementofcirculatingleucocytestothesiteof
inflammationandinjury.
Chemokinesare8-10kDproteinswith20-70%homology
inaminoacidsequence.
Chemokinesactlikechemoattractantcytokine.

4. ChemokineFunction

5. Proteinsareclassifiedintothechemokinefamilybasedontheir
structuralcharacteristics,notjusttheirabilitytoattractcells.
Theypossessconservedaminoacidsthatareimportantforcreatingtheir3-
dimensionalortertiarystructure,suchas(inmostcases)fourcysteinesthat
interactwitheachother.

7. Most chemokineshave 4 cysteineresidues which form disulphide bonds:
1. CC class –
The first two cysteinesare adjacent (example: MCP-1, RANTES)
2. CXC class-
The first two cysteinesare not adjacent (example: IL-8)
3. C class –
Only has 2 cysteinesnot 4 (example: Lymphotactin)
4. CX3C class –
Has 3 amino acids between the first two cysteinesand a different N-
terminal

8. Classification of chemokines

9. ChemokineReceptors
 Chemokinereceptorsaredefinedbyfunction,notstructure:-they
bindchemokinesandtransducesignal.
 Todateallknownchemokinereceptorsaremembersofthe7TM
GPCRsuperfamily,couplingtoGi.

10. CXC chemokines-
The two N-terminal cysteinesof CXC chemokines(orα-chemokines) are
separated by one amino acid, represented in this name with an "X”.
CXC chemokines
Glutamicacid leucine Glutamicacid leucine
argininepositive argininenegative
(ELR-Motif) (ELR without Motif)
Eg. IL-8 Eg. IL-8, GCP2,
GROα,β,Ƴ, MCP1-5,
RANTES.

11. ELR +ve:
meansthatinducethemigrationofneutrophilsandinteractwith
CXCR1andCXCR2chemokinereceptors.
eg.IL-8whichinducesneutrophilstoleavethebloodstreamandenter
intothesurroundingtissue.
ELR –ve:
meansthatinducemigrationoflymphocytesandinteractwithCXCR1to
CXCR7chemokinereceptors.
eg.IL-8,GCP2,GRO-α,β,Ƴ,MCP1-5$RANTES,
MCP(monocytechemoattractantproteins)
RANTES(regulateduponactivation,normalT-cellexpressedand
regulated).

12. CC Chemokine
Havingabilitytoinducemigrationofmonocytes,NK
cells, dendriticcells.
Eg.MCP-Monocytechemoattractantprotein(MCP)-1(CCL2)
specificallyattractsmonocytesandmemoryTcells.
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.

13. CXXXC chemokines-
in which 3 amino acid residue is present between two cysteines
residues.
Its also known as αchemokines
It work as both-
Chemoattractant
Adhesion molecule
Eg. fractalkine

14. C chemokines (or γ chemokines)
Unlikeallotherchemokinesinthatithasonlytwocysteines;one
N-terminalcysteineandonecysteinedownstream.
Twochemokineshavebeendescribedforthissubgroupandare
called:
1.XCL1(lymphotactin-α)and
2.XCL2(lymphotactin-β).

15. GDP+ G-protein subunit G-protein become inactive
binding of the chemokineligand, chemokinereceptors associate
with G-proteins then GDP GTP and the dissociation of the
different G protein subunits. The subunit called Gβactivates
anenzymeknown asPLC
Now, PLC cleaves PIP2 to form twosecond messenger molecules
calledIP3 and DAG
DAG activates another enzyme called PKC, and IP3 triggers the
release ofcalciumfrom intracellular stores.
Eg. IL8 binds to receptors CXCR1 &CXCR2, a rise of calcium
they activate PLD and that initiate intracellular signalling cascade
called MAP kinasepathway

17. Extravasation and chemokines/receptors

18. Regulation of integrines by
chemokines

19. 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

21. Schematicrepresentationoftheproposedmechanismoflymphocyte
recruitmentbyCXCR3-bindingchemokinesinendocrineautoimmunity.
ThyroidfollicularcellssecreteCXCL9,CXCL10,andCXCL11upon
stimulationwithIFN-γandTNF-α.Chemokines,inturn,drivechemotaxis
frombloodvesselsofTcellsexpressingthechemokinereceptorCXCR3.
ThisparticularsubsetofTcellsshowsaprevalentTh1immunephenotype
andproducesIFN-γ,thusperpetuatingtheinflammatoryprocess.
Thisloopofeventssupportstheactiveroleplayedbythyroidfollicularcells
andingeneralbycellsoftheglandularepithelium(asimilarmechanismhas
beendemonstratedforβ-cellsandadrenalcellsofthezonafasciculata)in
determiningthespecificityoftheinfiltratinglymphocytesandinmaintaining
theautoimmuneprocess.

22. Chronicrejectionofallograftsismediatedbyatandemof
alloantigen-dependentand-independentfactors.Theoxidative
stressinherenttothetransplantationprocedureoperateswithina
milieuofimmunologicfactorsthatcontributetothelater
developmentofchronicrejection.
Theaimofthisstudyisinvestigatetherolethatearlymyocardial
oxidativestresssignalingpathwaysmayhaveinthe
developmentofGCADusingrodenthearttransplantmodels.
Ourworkinghypothesisisthatmyocardialoxidativestress
followingcardiactransplantationcontributestothedevelopment
ofGCADviaabcl-2-associatedmechanism.

26. Intramoleculardisulfidebondstypicallyjointhefirstto
third,andthesecondtofourthcysteineresidues,numberedas
theyappearintheproteinsequenceofthechemokine.
Thefirsttwocysteines,inachemokine,aresituatedclose
togetherneartheN-terminalendofthematureprotein,withthe
thirdcysteineresidinginthecentreofthemoleculeandthe
fourthclosetotheC-terminalend.
Aloopofapproximatelytenaminoacidsfollowsthefirsttwo
cysteinesandisknownastheN-loop.
Thisisfollowedbyasingle-turnhelix,calledthreeβ-
strandsandaC-terminalα-helix.Thesehelicesandstrandsare
connectedbyturnscalled30s,40sand50sloops;thethirdand
fourthcysteinesarelocatedinthe30sand50sloops.