NF-κbexpressionpredictsclinicaloutcomefor nasalpolyposis* F.CardosoPereiraValera 1 ,R.Queiroz 2 ,C.Scrideli 2 ,L.GonzagaTone 2 , W.T.Anselmo-Lima 1 1 DepartmentofOphthalmology,OtorhinolaryngologyandHeadandNeckSurgery,SchoolofMedicineof RibeirãoPreto,UniversityofSãoPaulo,Brazil 2 DepartmentofPediatrics,SchoolofMedicineofRibeirãoPreto,UniversityofSãoPaulo,Brazil *Receivedforpublication:October2,2002;accepted:March15,2010 DOI:10.4193/Rhino09.161 INTRODUCTION Topical glucocorticoid (GC) is considered the drug of choice for the initial treatment of Nasal Polyposis (NP) (1,2) . Nevertheless, the rate for remission of NP with GC alone has been reported to be between 60.9 and 80% (2) . There are at least two main causes for GC treatment failure: a limited action of topical GC, either due to polyps extension (3) ,ordue to poor compliance to treatment (4) , and cell/molecular resis- tancetotheresponsetoGC (5,6) . When GC binds to its cytoplasmic GC Receptor (GR), the GC-GRcomplextranslocatesintothenucleus.Onceinsidethe nucleus, the GC-GR complex may exert two main forms of action: binding to glucocorticoid response elements (GRE), which are specific DNA domains that induce or inhibit tran- scription (7,8) ; or by inactivation of transcription factors (TF) such as NF-κB and AP-1 by direct interaction (8) . Since these TFscanalsoinhibitGR,thisphenomenonisknownasmutual antagonistic cross-action (9) . It is recognized that the main mechanism of anti-inflammatory action of GC is through TF inhibition (8) , and the transactivation of anti-inflammatory genes is considered to be of minimal importance in the anti- inflammatoryprocess. There are at least two well-described isoforms for GR (5,8) , which differ themselves only in their hormone-binding domain: GRα, the predominant isoform, which has a high affinity to GC and an elevated transcriptional activity, and GRβ, which is uncapable of interacting with GC, but interacts with GRα in the nucleus (8) .GRβ is considered to be an endogenous inhibitor of GRα (5) , and its increased expression hasbeenreportedinimmune-mediateddiseasessuchasulcer- ativecolitis,GC-resistantasthmaandrheumatoidarthritis. There is still some controversy about the real impact of GR isoform expression on GC resistance (10-12) , but higher expres- sion of GRβ, lower expression of GRα, or lower GRα/GRβ relation have been implicated as responsible for the increased cell resistance to GC (13) . Among these different mechanisms, an increased expression of GRβ has been consistently and extensively reported (5,6,14) in NP. Conversely, a lower GRα expression in nasal polyps compared to control nasal mucosa hasonlyrecentlybeendescribed (15) . Cell resistance to GC may also be mediated by other molecu- lar pathways (12) , such as: activation of p38 mitogen activated protein (MAP) kinase; histone deacetylase dysfunction; and a reciprocal inhibitory effect between GR and TF. As GR and Objective: To correlate clinical prognosis of patients with nasal polyps to the expression of p65, c-Fos, GRα and GRβ. Methods: A biopsy was obtained at the first evaluation of patients with nasal polyps, and at rhinoplasty for control mucosa. Patients with nasal polyps were treated with glucocorticoids and followed for at least 60 months. The expression of p65, c-Fos, GRα and GRβ was deter- mined by Real Time-PCR and correlated to clinical outcome. The end-point of resistance to glucocorticoid therapy was considered when surgery was indicated. Results: Patients with nasal polyps presented a higher expression of p65, a lower expression of GRα, and a lower GRα/GRβ ratio than control mucosa. The patients with nasal polyps who had a higher expression of p65 correlated with a poorer response to glucocorticoids, with a 3.5- fold higher risk for surgery. Conclusion: Patients with a higher p65 (NF-κB) expression at diagnosis were associated to a worse response to clinical treatment, suggesting one of the mechanisms of cell resistance to glu- cocorticoid treatment in patients with nasal polyps. Key-words: glucocorticoid, nasal polyps, glucocorticoid receptor, transcription factors, NF-κB SUMMARY ORIGINALCONTRIBUTION Rhinology,48,408-414,2010