Human IP-9: A keratinocyte-derived high affinity CXC-chemokine ligand for the IP-10/Mig receptor (CXCR3).
Chemokines and their receptors play a crucial part in the recruitment of leukocytes into inflammatory sites. The CXC chemokines IP-10 and Mig are selective attractants for activated (memory) T cells, the predominant cell type in skin infiltrates in many inflammatory dermatoses. The selectivity for activated T cells can be explained by the fact that both chemokines exert their effects through a common receptor, CXCR3, which is nearly exclusively expressed on activated T cells. The aim of this study was to identify biologically active CXCR3 ligands produced by keratinocytes. To that end, Chinese hamster ovary cells expressing a cDNA encoding CXCR3 were challenged with proteins obtained from interferon-gamma stimulated keratinocytes and subsequently monitored for effects on second messenger systems. By this approach we were able to isolate IP-10 and Mig, and in addition identified a novel highly potent ligand for the CXCR3 receptor, designated interferon-gamma-inducible protein-9, which proved to be chemotactic for activated T cells expressing CXCR3. Protein sequence and mass spectrometric analysis followed by molecular cloning of the cDNA encoding interferon-gamma-inducible protein-9, revealed that interferon-gamma-inducible protein-9 is a CXC chemokine with a molecular mass of 8303 Da. From a GenBank database query it became clear that interferon-gamma-inducible protein-9 is in fact the protein encoded by the cDNA sequence also known as beta-R1, H174 or I-TAC. In situ hybridization experiments showed that interferon-gamma-inducible protein-9 mRNA is expressed by basal layer keratinocytes in a variety of skin disorders, including allergic contact dermatitis, lichen planus, and mycosis fungoides suggesting a functional role for this chemokine in skin immune responses.
Tensen
C P
CP
Department of Dermatology, University Hospital Vrije Universiteit, Amsterdam/Leiden, Institute for Immunology, Amsterdam, The Netherlands.
Flier
J
J
Van Der Raaij-Helmer
E M
EM
Sampat-Sardjoepersad
S
S
Van Der Schors
R C
RC
Leurs
R
R
Scheper
R J
RJ
Boorsma
D M
DM
Willemze
R
R
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002633:Chemotaxis; D003001:Cloning, Molecular; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D017403:In Situ Hybridization; D007249:Inflammation / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism*; D008024:Ligands; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology
C515202:CXCL11 protein, human; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C104577:IP10-Mig receptor; D008024:Ligands; D012333:RNA, Messenger; D018121:Receptors, Cytokine