Evidence for altered activity of the IL-6 pathway in chronic rhinosinusitis with nasal polyps

Background

IL-6 activates T_H17 cells and regulates the response of B lymphocytes and regulatory T cells. The IL-6 receptor and the membrane protein, glycoprotein 130 (gp130), form an active signaling complex that signals through signal transducer and activator of transcription 3 (STAT3) and other signaling molecules. Both the IL-6 receptor (IL-6R) and gp130 can be found in soluble forms that regulate the pathway.

Objective

We measured IL-6 signaling components and IL-17 in chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP), CRS without nasal polyps (CRSsNP), and controls to assess the IL-6 pathway in CRS.

Methods

IL-6, soluble IL-6R, soluble gp130 (sgp130), and IL-17 were measured in sinus tissue extracts and in nasal lavage fluid by either cytokine bead array or ELISA. phosphoSTAT3 (p-STAT3) was determined by Western blot and by immunohistochemistry.

Results

IL-6 protein was significantly (P < .001) increased in CRSwNP compared with CRSsNP and controls. Soluble IL-6R was also increased in nasal polyp compared with control tissue (P < .01). Despite elevated IL-6 and sIL-6R, IL-17A, E, and F were undetectable in the sinus tissue from most of the patients with CRS and controls. p-STAT3 levels were reduced in the polyp tissue, possibly indicating reduced activity of IL-6 in the tissue. sgp130 was elevated in CRSwNP compared with CRSsNP and controls.

Conclusion

p-STAT3 levels are decreased in CRSwNP despite increased levels of IL-6 and sIL-6R and are associated with the absence of an IL-17 response. This may be a response to elevated levels of sgp130, a known inhibitor of IL-6 signaling. These results indicate that IL-6 and its signaling pathway may be altered in CRSwNP.

Key words: Chronic rhinosinusitis, nasal polyps, IL-6, IL-6 receptor, soluble glycoprotein 130, IL-17, phospho-STAT3

Abbreviations used: CRS, Chronic rhinosinusitis, CRSwNP, Chronic rhinosinusitis with nasal polyps, CRSsNP, Chronic rhinosinusitis without nasal polyps, Foxp3, Forkhead box protein 3, gp130, Glycoprotein 130, HIES, Hyper-IgE syndrome, IL-6R, IL-6 receptor, p-STAT3, phospho–Signal transducer and activator of transcription 3, sgp130, Soluble glycoprotein 130, sIL-6R, Soluble IL-6 receptor, STAT3, Signal transducer and activator of transcription 3, Treg, Regulatory T