RGD Reference Report - Inactivation of IL-6 and soluble IL-6 receptor by neutrophil derived serine proteases in cystic fibrosis. - Rat Genome Database

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Inactivation of IL-6 and soluble IL-6 receptor by neutrophil derived serine proteases in cystic fibrosis.

Authors: McGreal, EP  Davies, PL  Powell, W  Rose-John, S  Spiller, OB  Doull, I  Jones, SA  Kotecha, S 
Citation: McGreal EP, etal., Biochim Biophys Acta. 2010 Jul-Aug;1802(7-8):649-58. Epub 2010 May 7.
RGD ID: 4143275
Pubmed: PMID:20438838   (View Abstract at PubMed)
DOI: DOI:10.1016/j.bbadis.2010.04.005   (Journal Full-text)

The ability of IL-6 to signal via both membrane bound and soluble receptors is thought to explain the capacity of this cytokine to act in both the initiation and resolution of acute inflammatory responses. In cystic fibrosis (CF), poorly resolved neutrophillic inflammation of the lungs is a primary cause of morbidity and mortality. Expression of IL-6 has been reported to be low in CF lung secretions, despite ongoing inflammation, but the status of soluble IL-6 receptor (sIL-6R) in these patients is unknown. We hypothesised that sIL-6R may be an important potentiator of IL-6 activity in CF associated lung disease. IL-6, sIL-6R and sgp130 (a natural antagonist of responses mediated by the sIL-6R) were analysed by ELISA and Western blot in bronchoalveolar lavage fluid (BALF) from 28 paediatric CF patients and nine non-CF controls. Total cell counts in CF were four fold higher compared to controls (median: 1.4 x 10(6) cells/ml v. 0.35 x 10(6) cells/ml in controls) (p<0.001) and the infiltrate was dominated by neutrophils which were elevated by 89 fold (0.62 x 10(6) cells/ml v. 0.007 x 10(6) cells/ml in controls) (p<0.001). Other markers of inflammation such as IL-8 and MCP-1 were elevated 17.5 and 3.8 fold respectively (IL-8; median: 1122 pg/ml v. 64 pg/ml in controls, p<0.01 and MCP-1; median: 692 pg/ml v. 182 pg/ml in controls, p<0.05). IL-6, although present in 23/32 CF BALF specimens compared to 1/9 controls (p<0.01), was weakly expressed (median: 50 pg/ml). Expression of sIL-6R and sgp130 in CF was no different to control patients. We tested whether weak expression of all three molecules was due to degradation by CF BALF. Degradative activity was observed in association with BALF elastase activity and could be specifically blocked by serine protease inhibitors. Degradation of sIL-6R by purified serine proteases (elastase, cathepsin G and proteinase 3) was also observed leading to a loss of trans-signalling activity. Interestingly, sIL-6R was protected from proteolysis by interaction with IL-6. Our data identify and define a novel protease mediated deficiency of IL-6 signalling in the CF lung.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cystic fibrosis  IEP 4143275protein:increased expression:respiratory system fluid/secretionRGD 
cystic fibrosis  ISOCCL2 (Homo sapiens)4143275; 4143275protein:increased expression:respiratory system fluid/secretionRGD 
cystic fibrosis  IEP 4143275protein:increased expression:lungRGD 
cystic fibrosis  ISOIL6 (Homo sapiens)4143275; 4143275protein:increased expression:lungRGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccl2  (C-C motif chemokine ligand 2)
Il6  (interleukin 6)

Genes (Mus musculus)
Ccl2  (C-C motif chemokine ligand 2)
Il6  (interleukin 6)

Genes (Homo sapiens)
CCL2  (C-C motif chemokine ligand 2)
IL6  (interleukin 6)

Objects referenced in this article
Gene CCL13 C-C motif chemokine ligand 13 Homo sapiens

Additional Information