Summary During neuronal‐induced inflammation, mast cells may respond to stimuli such as neuropeptides in an FcεRI‐independent manner. In this study, we characterized human mast cell responses to substance P (SP), nerve growth factor (NGF), calcitonin gene‐related peptide (CGRP) and vasoactive intestinal polypeptide (VIP) and compared these responses to human mast cell responses to immunoglobulin E (IgE)/anti‐IgE and compound 48/80. Primary cultured mast cells, generated from CD34+ progenitors in the presence of stem cell factor and interleukin‐6 (IL‐6), and human cultured mast cells (LAD2) were stimulated with these and other stimuli (gastrin, concanavalin A, radiocontrast media, and mannitol) and their degranulation and chemokine production was assessed. VIP and SP stimulated primary human mast cells and LAD cells to degranulate; gastrin, concanavalin A, radiocontrast media, mannitol, CGRP and NGF did not activate degranulation. While anti‐IgE stimulation did not induce significant production of chemokines, stimulation with VIP, SP or compound 48/80 potently induced production of monocyte chemoattractant protein‐1, inducible protein‐10, monokine induced by interferon‐γ (MIG), RANTES (regulated on activation, normal, T‐cell expressed, and secreted) and IL‐8. VIP, SP and compound 48/80 also activated release of tumour necrosis factor, IL‐3 and granulocyte–macrophage colony‐stimulating factor, but not IL‐4, interferon‐γ or eotaxin. Human mast cells expressed surface neurokinin 1 receptor (NK1R), NK2R, NK3R and VIP receptor type 2 (VPAC2) but not VPAC1 and activation of human mast cells by IgE/anti‐IgE up‐regulated expression of VPAC2, NK2R, and NK3R. These studies demonstrate the pattern of receptor expression and activation of mast cell by a host of G‐protein coupled receptor ligands and suggest that SP and VIP activate a unique signalling pathway in human mast cells. These results are likely to have direct relevance to neuronally induced inflammatory diseases.

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.

Background-IL-13, a critical cytokine in allergy, is regulated by as-yet-elusive mechanisms.

Although it is widely accepted that glucocorticoids (GC) are a mainstay of the treatment of diseases characterized by airway inflammation, little is known about the effects of GC on local innate immunity. In this article, we report that respiratory epithelial cells manifested a local “acute phase response” after stimulation with TLR activation and TNF-α and that GC spared or enhanced the epithelial expression of molecules that are involved in host defense, including complement, collectins, and other antimicrobial proteins. As expected, GC inhibited the expression of molecules responsible for inflammation such as cytokines (IFNβ and GM-CSF) and chemokines (RANTES and IL-8). Studies using Western blotting, EMSA, and functional analysis indicated that the selective effects of GC are mediated through activation of the transcription factor C/EBP. Knockdown of C/EBPβ by small interfering RNA blocked the enhancement by GC of host defense molecule expression but had no effect on inflammatory gene expression. These results suggest that GC spare or enhance local innate host defense responses in addition to exerting anti-inflammatory actions. It is possible that the known ability of GC to reduce the exacerbation of diseases in which infectious organisms serve as triggering factors (e.g., asthma, allergic bronchopulmonary aspergillosis, and chronic obstructive pulmonary disease) may result in part from enhanced innate immune responses in airway mucosa.