C-C chemokine ligand 2 gene expression in nasal polyp fibroblasts: possible implication in the pathogenesis of nasal polyposis (original) (raw)
Related papers
Allergy, 2003
Although the mechanisms that underlie nasal polyposis are not fully understood, the clinical and morphological manifestations of this disorder have been well characterized. Nasal polyps (NPs) are transparent, pale gray edematous projections that originate from nasal ethmoid mucosa in the vicinity of the middle turbinate (1). Inflammation is a prominent feature of NPs. Histological studies have shown that about 80-90% of the polyps are characterized by abundant eosinophils, CD8+ T cells, and mast cells (1). Among these cells, eosinophils play a prominent role in the pathogenesis of NPs (2). For example, it has been shown that eosinophils promote epithelial proliferation, matrix generation, and tissue remodeling through the release of cytokines such as transforming growth factor-alpha, transforming growth factor-beta, and granulocyte-macrophage colony stimulating factor (GM-CSF) (2-4). Moreover, activated eosinophils may cause tissue damage through the release of reactive oxygen metabolites and cytotoxic granulederived proteins such as major basic protein (5). Eosinophil recruitment from the circulation involves a series of separate processes. Initial adhesion to endothelium and transendothelial migration is dependent upon the expression of complementary pairs of adhesion molecules on eosinophils and activated endothelial cells. Subsequent migration across the extracelular matrix towards the inflammatory site is thought to be directed by chemotactic stimuli. A number of eosinophil chemoattractants have been described including cytokines such as interleukin (IL)-5 and GM-CSF, which are relatively weak stimuli, and small molecules such as platelet activating factor and C5a, which are potent but not selective as they also attract neutrophils (6). Members of the chemokine family including RANTES/CCL5, MCP-3/CCL7, and MCP-4/CCL13 are potent eosinophil attractants but not selective as they also attract lymphocytes and monocytes. In contrast, the eotaxins (eotaxin-1,-2 and,-3) are selective eosinophil attractants (7). These chemokines also attract a small population of lymphocytes. While eotaxin-1/CCL24 has been extensively investigated in NPs (8-10), the role of eotaxin-2/CCL24 and eotaxin-3/CCL26 in this disease has not been well defined. Eotaxin-2/CCL24 was identified in early 1997 by random sequencing of expressed sequence tags in a cDNA library from activated human monocytes (11), and subsequently shown to be a potent eosinophil attractant (12). Increased eotaxin-2/CCL24 mRNA expression has been reported in biopsies derived from patients suffering from NPs (10). Interestingly, in this study (10), eotaxin-2/CCL24 mRNA expression showed Background: Eotaxin-2/CCL24 is a potent eosinophil attractant that has been implicated in the recruitment of eosinophils in allergic disease. We have investigated whether the cytokines interleukin (IL)-4, IL-13, and interferon (IFN)gamma regulate eotaxin-2/CCL24 in nasal polyps. Methods: Nasal polyps were cultured in the presence of the cytokines described above and the concentration of eotaxin-2/CCL24 was measured in the culture supernatant. Results: IL-4 was found to be the major stimulus for eotaxin-2/CCL24 production from nasal polyps followed by IL-13 and IFN-gamma. IL-4 induced eotaxin-2/CCL24 in a dose-dependent manner with concentrations as low as 0.1 ng/ml being able to induce eotaxin-2/CCL24. By immunohistochemistry, eotaxin-2/CCL24 immunoreactivity was localized to mononuclear cells in the IL-4 stimulated nasal polyp tissue. Interestingly, nasal turbinates obtained from patients suffering from nonallergic rhinitis (vasomotor rhinitis) were also found to release eotaxin-2/CCL24 both spontaneously and following cytokine stimulation with IL-4 and IFN-gamma being major inducers of this cytokine. Conclusions: All together these findings suggest that Th1 and Th2 cytokines may regulate eotaxin-2/CCL24 production in nasal polyps and nonallergic rhinits.
Inducible Cyclooxygenase and Interleukin 6 Gene Expressions in Nasal Polyp Fibroblasts
Archives of Otolaryngology–Head & Neck Surgery, 2002
Background: Inflammation is believed to be related to the pathogenesis of nasal polyp (NP). Inducible cyclooxygenase (COX-2) and interleukin (IL) 6 are important mediators of inflammation. However, no information is available regarding the expression of these mediators in nasal polyp fibroblasts (NPFs). The inductive effects of proinflammatory cytokines (IL-1␣ or tumor necrosis factor ␣) alone or in combination with prostaglandin E 2 on IL-6 and COX-2 messenger RNA (mRNA) synthesis in NPFs were investigated. Design: The expressions of IL-6 and COX-2 mRNAs in NPFs and in 34 surgical specimens of NP were detected by Northern blot and in situ hybridization. Results: Significant amounts of constitutive IL-6 and COX-2 mRNAs were produced in NPFs. Cytokines induced IL-6 and COX-2 mRNA synthesis in NPFs. Meloxicam (a specific COX-2 inhibitor) suppressed the induc
Journal of Allergy and Clinical Immunology, 2012
Background-Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with Th2dominant inflammation including eosinophilia, in contrast to non-polypoid CRS (CRSsNP). Chemokine CCL18/PARC (pulmonary and activation regulated chemokine) is known to recruit naïve T cells, B cells, and immature dendritic cells, as well as activate fibroblasts. CCL18is thought to be involved in Th2-related inflammatory diseases including asthma and atopic dermatitis. Objectives-The objective of this study was to investigate the expression of CCL18 in patients with CRS. Methods-Using nasal polyp tissue (NP) and uncinate tissue (UT) from controls and patients with CRS, we examined the expression of CCL18 mRNA by real-time PCR and measured CCL18 protein by ELISA, western blot and immunofluorescence. Results-Compared to UT tissue in control subjects, CCL18 mRNA was significantly increased in NP (p<0.001) and UT (p<0.05) from patients with CRSwNP but not in UT from patients with CRSsNP. Similarly, CCL18 protein was elevated in NP and UT from CRSwNP and levels were even higher in Samter's triad patients. Immunohistochemical analysis revealed CCL18 expression in inflammatory cells and CCL18 + cells were significantly increased in NP. Immunofluorescence data showed co-localization of CCL18 in CD68 + /CD163 + /macrophage mannose receptor + M2 macrophages and tryptase + mast cells in NP. Levels of CCL18 correlated with markers of M2 macrophages but not with tryptase, suggesting that M2 macrophages are a major CCL18producing cells in NP.
Expression of transcription factors NF-κB and AP-1 in nasal polyposis
Clinical & Experimental Allergy, 2008
The treatment and prognosis of nasal polyposis (NP) may be influenced by transcription factors, but their expression is poorly understood. To determine the expression of transcription factors [(nuclear factor-kappaB) NF-kappaB and (activator protein) AP-1], cytokines [IL-1beta, TNF-alpha and (granulocytes and macrophage colony-stimulating factor) GM-CSF], growth factor (b-FGF), chemokine (eotaxin-2) and adhesion molecule (ICAM-1) in NP in comparison with nasal mucosa controls. Methods Cross-sectional study. Twenty biopsies of nasal polyps were compared with eight middle turbinate biopsies. p65, c-Fos, IL-1beta, TNF-alpha, ICAM-1, b-FGF, eotaxin-2 and GM-CSF were analysed through RQ-PCR, and p65 and c-Fos were also analysed through Western blotting. NF-kappaB expression was increased in patients with NP when compared with control mucosa (P<0.05), whereas AP-1 expression did not differ significantly between groups. Expressions of IL-1beta, eotaxin-2 and b-FGF were also increased in patients with NP compared with controls (P<0.05). The transcription factor NF-kappaB is more expressed in NP than in control mucosa. This is important in NP because NF-kappaB can induce the transcription of cytokines, chemokines and adhesion molecules, which play an important role in the inflammatory process. Moreover, transcription factors influence the response to corticosteroids, which are the basis of NP treatment. Transcription factor AP-1 does not seem to have a significant role in the pathological process.
Cyclooxygenase 1 and cyclooxygenase 2 expression is abnormally regulated in human nasal polyps
Journal of Allergy and Clinical Immunology, 2002
Background: There is evidence that impairment of prostanoid metabolism might be involved in the pathogenesis of nasal polyps (NPs). Prostanoids are synthesized by 2 cyclooxygenase (Cox) enzymes, one constitutive (Cox-1) and another inducible (Cox-2). Objective: The aim of these studies was to investigate Cox-1 and Cox-2 regulation in NPs of aspirin-tolerant human patients compared with that seen in nasal mucosa (NM). Methods: Cultured explants from human NPs and healthy mucosa from patients undergoing polypectomy and corrective nasal surgery, respectively, were examined for Cox-1 and Cox-2 expression by means of semiquantitative competitive PCR and Western blotting. Results: Cox-1 mRNA was spontaneously upregulated in cultured NM but not in NPs. A spontaneous but delayed upregulation of Cox-2 mRNA was found in NPs (24 hours) compared with that seen in NM (6 hours). After cytokine stimulation (IFN-γ, IL-1β, and TNF-α), the induction of Cox-2 mRNA and protein was also faster in NM (1 hour) than in NPs (4 hours). Conclusion: These data showing an abnormal regulation of Cox-1 and Cox-2 in NPs from aspirin-tolerant patients reinforce the concept that prostanoid metabolism might be important in the pathogenesis of inflammatory nasal diseases and suggest a potential role for this alteration in the formation of NPs. (J Allergy Clin Immunol 2002;109:824-30.)
Upregulation of COX-1 and COX-2 in nasal polyps in cystic fibrosis
Thorax, 2006
Background: Since abnormalities in prostanoid metabolism occur in the lower airway of patients with cystic fibrosis (CF), it is likely that they could also be detected in the nose. Methods: The degree of mRNA and protein expression of cyclo-oxygenase (COX) enzymes 1 (COX-1) and 2 (COX-2) was examined using quantitative reverse competitive polymerase chain reaction (RT-PCR) and Western blot analysis in the nasal polyps from 10 patients with CF, nasal polyps from 10 non-CF patients and 11 nasal mucosa specimens. The results are presented as 10 6 cDNA molecules/mg total RNA and the densitometric ratio between protein and b-actin. Results: COX-1 mRNA levels were significantly higher in CF nasal polyps (median 2.34, 25-75th percentiles 1.6-3.2) than in the nasal mucosa (0.78, 0.11-1.21), while there was no difference with non-CF nasal polyps (1.11, 0.80-3.15). COX-1 protein levels were significantly higher in CF nasal polyps (3.63, 2.71-4.27) than in nasal mucosa (1.55, 0.66-2.33) and non-CF nasal polyps (2.19, 1.72-3.68). COX-2 mRNA was significantly higher in CF nasal polyps (3.34, 2.42-7.05) than in nasal mucosa (1.69, 0.19-3.50). No differences were found in COX-2 mRNA expression between CF and non-CF polyps (1.38, 0.12-6.07). COX-2 protein levels were also significantly higher in CF nasal polyps (0.23, 0.04-0.34) than in non-CF nasal polyps (0.011, 0.009-0.016) or nasal mucosa (0.014, 0.014-0.016). Conclusions: Upregulation in the expression of COX-1 and COX-2 could explain the high production of prostanoids reported in CF. These findings raise questions regarding the potential use of selective or nonselective COX-2 non-steroidal anti-inflammatory treatment in CF.
Increased expression of the chemokine CCL23 in eosinophilic chronic rhinosinusitis with nasal polyps
Journal of Allergy and Clinical Immunology, 2011
Background-Chronic rhinosinusitis (CRS) is a heterogeneous chronic disease characterized by local inflammation of the sinonasal tissues. The pathogenesis of CRS remains controversial but it has been associated with the accumulation of various immune and inflammatory cells in sinus tissue. Objectives-The objective of this study was to investigate the expression of chemokine CCL23, known to bind to CCR1 and recruit monocytes, macrophages, and dendritic cells, in patients with CRS. Methods-We collected nasal tissue from patients with CRS and control subjects. We assayed mRNA for CCL23 by using real-time PCR and measured CCL23 protein by ELISA, immunohistochemistry and immunofluorescence. Results-CCL23 mRNA was significantly elevated in nasal polyps from patients with polypoid CRS (CRSwNP) (p<0.05) compared to inferior turbinate and uncinate tissue from patients with CRS or control subjects. CCL23 protein was also elevated in nasal polyps, although these levels were not statistically significant. Immunohistochemical analysis revealed CCL23 expression in mucosal epithelial cells and inflammatory cells, but accumulation of CCL23 positive inflammatory cells occurred only in nasal polyps. Immunofluorescence data showed CCL23 colocalization with ECP positive eosinophils. The concentration of CCL23 in nasal polyps positively correlated with the concentration of ECP, suggesting that eosinophils are major CCL23 producing
American Journal of Rhinology & Allergy, 2011
Background The pathogenesis of nasal polyps (NPs) is incompletely understood. The aim of this study was to investigate the distribution of inflammatory cells, adhesion molecules, intermediate filaments, and chemokine receptors in subgroups of NP patients. Methods In total, 35 patients were enrolled (group 1, 10 patients with Samter syndrome; group 2, 10 patients with diffuse polyposis without signs of Samter syndrome; group 3: 5 patients with solitary nasal polyps; group 4, 10 controls). Immunohistochemical staining was performed for CD105, CD106, CD62E, CD4, CD8, CXCR4, CD147, CD90, CD104, BF45, vimentin, pancytokeratin, and muscle-specific actin (MSA) in all patients’ specimens. Results Expression of CD4, CD8, and CD106 were similar between the groups. Number of patients expressing CD4 in groups 1, 2, and 3 were higher than the controls. Number of patients expressing CD8 antigen were significantly higher in all three groups than in the control group. Expression of CD147 in groups ...
Journal of Allergy and Clinical Immunology, 2008
The polypoid form of chronic rhinosinusitis (chronic rhinosinusitis with nasal polyps [CRSwNP]) is a highly prevalent disease that often requires surgical intervention for treatment. Nasal polyps contain large quantities of B lymphocytes and immunoglobulin as well as eosinophils.The objective of this study was to investigate the expression of B cell–activating factor of the TNF family (BAFF), an important regulator of class-switch recombination and immunoglobulin production, in patients with chronic rhinosinusitis (CRS).We collected nasal tissue and nasal lavage fluid from patients with CRS and control subjects. We assayed mRNA for BAFF and B-lymphocyte markers, CD20 and transmembrane activator and calcium-modulator and cyclophilin ligand interactor, by using real-time PCR, and assayed BAFF protein by using ELISA and immunohistochemistry.BAFF mRNA was significantly increased in nasal polyps from patients with CRSwNP (P < .001) compared with inferior turbinate tissue from patients with CRS or healthy subjects. BAFF protein was also elevated in polypoid tissue and nasal lavage from patients with CRSwNP. Immunohistochemistry showed considerable BAFF staining in mucosal epithelial cells in nasal polyps along with unidentified cells in the lamina propria. Expression of mRNA for BAFF in sinonasal tissue was significantly correlated with CD20 and transmembrane activator and CAML interactor in sinus tissue. IgA, an immunoglobulin isotype known to activate eosinophils, was also significantly elevated in the polypoid tissue.Overproduction of BAFF in nasal polyps may contribute to the pathogenesis of CRSwNP via the local induction of IgA and activation of eosinophils.