title: Differential regulation of neutrophil-activating chemokines by IL-6 and its soluble receptor isoforms.
abstract: Interleukin-6 signaling via its soluble receptor (sIL-6R) differentially regulates inflammatory chemokine expression and leukocyte apoptosis to coordinate transition from neutrophil to mononuclear cell infiltration. sIL-6R activities may, however, be influenced in vivo by the occurrence of two sIL-6R isoforms that are released as a consequence of differential mRNA splicing (DS) or proteolytic cleavage (PC) of the cognate IL-6R (termed DS- and PC-sIL-6R). Using human peritoneal mesothelial cells and a murine model of peritoneal inflammation, studies described in this work have compared the ability of both isoforms to regulate neutrophil recruitment. In this respect, DS- and PC-sIL-6R were comparable in their activities; however, these studies emphasized that IL-6 trans signaling differentially controls neutrophil-activating CXC chemokine expression. In vitro, stimulation of mesothelial cells with IL-6 in combination with either DS-sIL-6R or PC-sIL-6R showed no induction of CXC chemokine ligand (CXCL)1 (GRO alpha) and CXCL8 (IL-8), whereas both isoforms enhanced CXCL5 (ENA-78) and CXCL6 (granulocyte chemotactic protein-2) expression. Moreover, when complexed with IL-6, both isoforms specifically inhibited the IL-1 beta-induced secretion of CXCL8. These findings were paralleled in vivo, in which induction of peritoneal inflammation in IL-6-deficient (IL-6(-/-)) mice resulted in enhanced keratinocyte-derived chemokine and macrophage-inflammatory protein-2 (the murine equivalent of CXCL1 and CXCL8) levels, but reduced LPS-induced CXC chemokine (the murine equivalent of CXCL5) expression. Reconstitution of IL-6 signaling in IL-6(-/-) mice with IL-6 and its soluble receptor isoforms corrected this chemokine imbalance and suppressed overall neutrophil infiltration. These data confirm that sIL-6R-mediated signaling primarily limits neutrophil influx; however, induction of CXCL5 and CXCL6 may regulate other neutrophil responses.
authors.affiliation: Cardiff School of Biosciences, Cardiff University, Cardiff, Wales, United Kingdom.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Hurst
authors.forename: Mari A
authors.initials: MA
authors.lastname: Nowell
authors.forename: Dean A
authors.initials: DA
authors.lastname: Harris
authors.forename: Sankichi
authors.initials: S
authors.lastname: Horiuchi
authors.forename: Llinos W
authors.initials: LW
authors.lastname: Morgan
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wilkinson
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000328:Adult; D017398:Alternative Splicing; D020816:Amino Acid Motifs; D000818:Animals; D002478:Cells, Cultured; D018932:Chemokine CCL2; D018925:Chemokines / Q000096:biosynthesis* / Q000502:physiology; D019743:Chemokines, CXC / Q000096:biosynthesis; D010450:Endopeptidases / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018375:Neutrophil Activation / Q000235:genetics / Q000276:immunology*; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010537:Peritoneum / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000276:immunology / Q000378:metabolism; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D012995:Solubility
chemical_list: C111835:CCL2 protein, human; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D019743:Chemokines, CXC; D015850:Interleukin-6; D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D010450:Endopeptidases