title: CXCR3 axis in patients with primary biliary cirrhosis: a possible novel mechanism of the effect of ursodeoxycholic acid.
abstract: The CXC chemokines, monokine induced by interferon (IFN)-gamma (MIG) (CXCL9), IFN-gamma-induced protein 10 (IP-10) (CXCL10) and IFN-inducible T cell alpha chemoattractant (I-TAC) (CXCL11), are known to attract CXCR3- (CXCR3A and CXCR3B) T lymphocytes. We investigated MIG, IP-10 and I-TAC mRNAs expression by semi-quantitative multiplex reverse transcription-polymerase chain reaction (RT-PCR) in liver biopsies obtained from patients with a first diagnosis of primary biliary cirrhosis [(PBC) = 20] compared to patients with normal liver biopsy [normal controls (NCs) = 20]. Chemokine production was assessed by enzyme-linked immunosorbent assay (ELISA) in serum. Measurements were repeated 6 months after ursodeoxycholic acid (UDCA) treatment in PBC patients. CXCR3A and CXCR3B mRNAs expression was examined in immunomagnetically sorted CD3(+) peripheral blood lymphocytes (PBL) pre- and post-treatment by RT-PCR. Flow cytometry was used to evaluate the expression of CXCR3(+) PBLs of NCs and PBC patients. A marked mRNA expression of MIG and IP-10 was found in PBC patients. I-TAC mRNA was not detected. In serum of PBC patients there was a significant increase of MIG and IP-10 compared to NCs. Interestingly, there was a significant reduction of these proteins in patients' serum after UDCA treatment. I-TAC was not statistically different between groups. CXCR3A mRNA expression was found in PBLs from PBC patients as well as in NCs. CXCR3B mRNA was expressed in four of 20 (19%) NCs and 20 of 20 PBC patients. Flow cytometry revealed a significantly lower CXCR3 expression in NCs (13·5%) than in PBC (37·2%), which was reduced (28·1%, P < 0·01) after UDCA administration. These data suggest a possible role for CXCR3-binding chemokines and their receptor in the aetiopathogenetic recruitment of lymphocytes in PBC and a new mechanism of action for UDCA.
authors.affiliation: Department of Gastroenterology and Hepatology, Liver Research Laboratory, University of Crete, Heraklion, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Manousou
authors.forename: G
authors.initials: G
authors.lastname: Kolios
authors.forename: I
authors.initials: I
authors.lastname: Drygiannakis
authors.forename: M
authors.initials: M
authors.lastname: Koulentaki
authors.forename: K
authors.initials: K
authors.lastname: Pyrovolaki
authors.forename: A
authors.initials: A
authors.lastname: Voumvouraki
authors.forename: G
authors.initials: G
authors.lastname: Notas
authors.forename: L
authors.initials: L
authors.lastname: Bourikas
authors.forename: H A
authors.initials: HA
authors.lastname: Papadaki
authors.forename: E
authors.initials: E
authors.lastname: Kouroumalis
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D054357:Chemokine CXCL10 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054371:Chemokine CXCL11 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D002756:Cholagogues and Choleretics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D054367:Receptors, CXCR3 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C114753:CXCL10 protein, human; C515202:CXCL11 protein, human; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D002756:Cholagogues and Choleretics; D020033:Protein Isoforms; D012333:RNA, Messenger; D054367:Receptors, CXCR3; D014580:Ursodeoxycholic Acid