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

Abstract

Background: IL-6 activates T(H)17 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.

Figure 1

Assessment of IL-6 and soluble IL-6 receptor (sIL-6R) levels in CRS by ELISA. A, IL-6 levels were increased in nasal polyps compared to sinus tissues from controls and CRSsNP. B, sIL-6R levels were increased in the polyp tissue compared to sinus tissue from controls. Levels were marginally increased (p=0.06) in CRSwNP compared to CRSsNP.

Figure 2

A, Representative western blot of p-STAT3 and total STAT3 in nasal polyps and controls. B, Densitometric analysis of p-STAT3 from four controls and six CRSwNP subjects shown in A. C, Densitometric analysis of p-STAT3 from seven controls and nine CRSwNP subjects. D, Representative western blot of p-STAT3 in nasal polyp (n=3) and inferior turbinate tissue (n=3) within the same CRSwNP patients. E, (1) Isotype control antibody staining in control tissue. (2) Representative immunostaining for p-STAT3 in control tissue.

Figure 3

Soluble glycoprotein 130 (sgp130) levels are increased in polyp tissue compared to sinus tissue from controls by ELISA.