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

Abstract

Background Interleukin 6 (IL-6) activates Th17 cells and regulates the response of B-lymphocytes and T regulatory cells. The IL-6 receptor and the membrane protein, gp130, form an active signaling complex that signals through 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 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 (sIL-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<0.001) increased in CRSwNP compared to CRSsNP and controls. sIL-6R was also increased in nasal polyp compared to control tissue (p<0.01). 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 to 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. Clinical implications The IL-6 signaling pathway may have a pathogenic role in CRSwNP.

A Proposed Model to Study Immunologic Changes during Chronic Rhinosinusitis Exacerbations: Data from a Pilot Study

“…[15][16][17][18][19][20] A recent study identified activation of IL-6 (and a possible signaling defect in the IL-6 pathway) in patients with CRS and nasal polyps compared with normal controls. 21 These findings suggest a host characteristic, when coupled with an environmental exposure such as viral URTI that promotes IL-6 production, could potentially explain a …”

International Consensus Statement on Allergy and Rhinology: Rhinosinusitis

“…334,[519][520][521] A precise molecular pathway for this defect has not been proposed, but the cytokine IL-22 and its receptor IL-22R are key regulators of mucosal host defense, 522 acting in large part through the transcription factor STAT 3. 523,524 Diminished expression of IL-22R 525 and blunting of the STAT 3 pathway 526 have been reported; these defects appear to be associated with CRS broadly, and are not specific for the presence or absence of NPs. 527 Taken together, these data provided support for the hypothesis that a primary sinonasal innate immune defect may predispose to the development of CRS.…”

“…The elevated IL-6 levels might suggest viral infection 1109 or might be related to the altered IL-6 pathway described in patients with CRS. 526 Bacterial infection also contributes to acute exacerbations and acute purulent episodes in the scenario of underlying chronic inflammatory changes associated with CRS. The frequent presence of biofilm-forming organisms represents a large reservoir for opportunistic infections.…”

Peripheral Blood and Tissue T Regulatory Cells in Chronic Rhinosinusitis

“…28 IL-6 plays important roles in regulating Treg and T H 17 differentiation by inhibiting FoxP3, which, in turn, leads to diminished inhibition of the retinoic acid-related orphan receptor ROR␥T and consequently expansion of T H 17 cells. 28 We failed to detect significant amounts of IL-17A, a key cytokine produced by the T H 17 cells in all of our samples, and we did not count T H 17 cells. Nevertheless, the elevation of IL-6 may indicate another mechanism whereby Treg function is inhibited in CRS via a T H 17 mechanism.…”