The cytokine Interleukin-4 (IL-4) plays a crucial role in the pathophysiology and progression of asthma and other atopic diseases. Its activities are signaled into the cells upon binding to and signaling through a shared receptor complex composed of the subunits IL-4Rα and common γc. Another cytokine, Interleukin-13 shares many functions with IL-4. This can be explained by the fact that both, IL-4 and IL-13, can signal via a shared receptor complex comprising the IL-4R and the IL-13R1 subunit. Therefore, the IL-4Rα receptor subunit has become a highly promising drug target, since it mediates IL-4 and IL-13 responses and blocking IL-4Rα will abrogate IL-4 as well as IL-13 effector functions. Currently, an IL-4 based mutein (Pitrakinra), acting as a dual IL-4/IL-13 receptor antagonist is in clinical development. This work describes the generation and production of biologically active IL-4 muteins, which contain a single additional engineered cysteine. The introduction of a free thiol group allows site-specific chemical modification. The muteins were expressed in E. coli in insoluble form, refolded and purified. The thiol group of the mutein was protected as mixed disulfide with the tripeptide glutathione. A first attempt to chemically reduce the engineered cysteine residue failed, because the three native disulfide bonds of IL-4 exhibit a similar reactivity and chemical reduction of the native disulfide resulted in full deactivation and precipitation of the IL-4 protein. Therefore, an enzymatic approach was developed which specifically reduces the mixed disulfide bonds with an attached glutathion moiety and thus leaves the native structurally essential disulfide bonds unaltered. For optimization, four different IL-4 cysteine muteins with four cysteine residues introduced at positions close to the IL-4Rα binding site were tested and their reduction rates by glutaredoxin was determined. The enzymatic reduction occured at different rates for all four muteins indicating that accessibility is an important influence and must be determined individually for each mutant protein. After optimization of the pH value and particularly the reaction time, all muteins could be prepared with the engineered thiol group being released in reasonable yield. The proteins exhibiting the free thiol group were then modified by N-ethylmaleimide (NEM) or maleimido-PEG. The effects of these modifications at different positions on binding to IL-4R were measured employing SPR biosensor technology. In the second project of this study, foldamers, which represent a new class of stable, compactly folded biomolecules and can specifically interact with proteins and nucleic acids, were examined to identify their potential as new drugs to interfere with IL-4 activities. Fragment-based drug discovery offers great promise for providing new starting points for drug discovery and facilitates the lead optimization. As foldamers equipped with a thiol-group for tethering could not to be produced; only the effect of foldamers present in a synthesized foldamer library on the binding to IL-4R could be tested. Two libraries containing different foldamers based on aromatic amide were synthesized by Michael Grotz and Dr. Michael Deligny and tested in our lab for their capability to disrupt the ligand-receptor interaction of IL-4 and its receptor IL-4Rα [ECD] using surface plasmon resonance technology. None of the studied foldamers could specifically inhibit the IL-4/IL-4Rα interaction. Some foldamers showed non-specific binding. The study presented here shows the design and production of a potentially new type of IL-4 antagonists, which employ site-specific chemical modification to exert their antagonistic function. / Das Zytokin Interleukin-4 (IL-4) spielt eine entscheidende Rolle in der Entstehung und Pathophysiologie von Asthma und anderen atopischen Krankheiten. Seine Aktivitäten können in die Zelle durch die Bindung an einen Rezeptorkomplex übertragen werden, welcher aus den Untereinheiten IL-4Rα und γc besteht. Interleukin-13 (IL-13), ein verwandtes Zytokin, und IL-4 besitzen viele gemeinsame Funktionen. Das kann dadurch erklärt werden, dass IL-4 wie auch IL-13 ihre Signale über einen gemeinsamen Rezeptorkomplex übertragen können, der aus der IL-4R und der IL-13R1 Untereinheit besteht. Die IL-4R Untereinheit ist ein vielversprechendes Zielmolekül für die Entwicklung von Pharmaka, da sie IL-4 und IL-13 Reaktionen vermittelt. Durch Blockieren von IL-4R werden die Aktivitäten von IL-4 sowie IL-13 unterdrückt. Ein IL-4 basiertes Doppelmutein (Pitrakinra), welches als Gegenspieler zu IL-4 und IL-13 Rezeptoren fungiert, befindet sich derzeit in der klinischen Entwicklung. In dieser Arbeit wird die Bildung und Produktion von biologisch aktiven IL-4 Muteinen mit einem einzelnen zusätzlich eingefügten Cysteinrest beschrieben. Die Einführung einer freien Thiol-Gruppe ermöglicht ortsspezifische chemische Modifizierungen. Ein „Tethering“ Ansatz sollte dann auch eine sehr schwach Bindung von thiol-reaktiven Verbindungen an IL-4 messbar machen. Die Muteine wurden in unlöslicher Form in E. coli exprimiert, zurückgefaltet und auf gereinigt. Dabei wurde die Thiolgruppe des Muteins als Disulfid mit dem Tripeptid Glutathion geschützt. Erste Versuche gezielt den eingeführten Cysteinrest selektiv chemisch zu reduzieren schlugen fehl, da die drei proteineigenen Disulfidbrücken von IL-4 eine ähnliche Reaktivität zeigten, und die Reduktion zur vollständigen Desaktivierung und Fällung des IL-4 Proteins führte. Daher wurde ein enzymatischer Ansatz entwickelt, der gezielt die Disulfidbrücke zum Glutathionrest reduziert und die proteineigenen strukturell essentiellen Disulfidbrücken unverändert lässt. Zur Optimierung wurden vier verschiedene IL-4 Cystein-Muteine mit Cysteinresten an verschiedenen Positionen nahe der IL-4Rα Bindungsstelle getestet und die Reduktionsgeschwindigkeit in Gegenwart von Glutaredoxin bestimmt. Die enzymatische Reduktion verlief für alle vier Muteine mit verschiedenen Geschwindigkeiten. Dies deutet darauf hin, dass die Zugänglichkeit der Disulfidgruppe einen wichtigen Einfluss besitzt. Die Reduktionsbedingungen mussten daher für jedes Mutein neu bestimmt werden. Nach Optimierung des pH Wertes und insbesondere der Reaktionszeit konnten alle Muteine mit einer freien Thiolgruppe in angemessener Ausbeute erhalten werden. Die Proteine mit jeweils einer freien Thiolgruppe wurden daraufhin mit N-Ethylmaleinimid (NEM) oder Maleimido-PEG modifiziert. Die Effekte der Modifizierung an verschiedenen Positionen des IL-4 auf die Bindung an IL-4R wurden mit Hilfe der SPR-Spektroskopie (Oberflächen Plasmon Resonanz Spektroskopie) gemessen. Im zweiten Teil dieser Arbeit wurde die Interaktion von Foldameren mit der IL-4Ra Rezeptorkette untersucht. Foldamere stellen eine neue Klasse von stabilen, kompakt gefalteten Biomolekülen dar, die möglicherweise spezifisch mit Proteinen und Nukleinsäuren wechselwirken können. Es sollten Vorversuche durchgeführt werden um zu sondieren, ob aus Foldameren Hemmstoffe für IL-4 und IL-13 entwickelt werden können. Da Foldamere mit einer Thiolgruppe zur Anbindung (Tethering) an IL-4 nicht hergestellt werden konnten, wurden zunächst nur nichtreaktive Foldamare aus einer synthetisierten Foldamer-Bibliothek getestet. Zwei Bibliotheken mit verschiedenen auf aromatischen Amiden basierenden Foldameren wurden von Michael Grotz und Dr. Michael Deligny synthetisiert und von mir mit Hilfe der SPR Spektroskopie auf ihre Fähigkeit getestet, die Ligand-Rezeptor Wechselwirkung von IL-4 und derIL-4Rα Rezeptoruntereinheit zu unterbinden. Keines der untersuchten Foldamere konnte die IL-4/IL-4Rα Wechselwirkung spezifisch hemmen. Einige Foldamere zeigten eine unspezifische Bindung. Die hier dargestellten Studien zeigen das Design und die Herstellung eines potentiell neuen Typs von Gegenspieler zu IL-4, welcher ortsspezifische chemische Modifikationen ausnutzt um seine antagonistische Funktion zu erfüllen.

Myocardial infarction (MI) occurs following acute thrombotic occlusion of a coronary artery, and triggers a robust inflammatory response. Within hours, neutrophils are recruited to the infarcted myocardium followed by the infiltration of pro-inflammatory Ly6Chi monocytes. Transition from the pro-inflammatory macrophage phenotype (M1) to an anti-inflammatory, pro-resolution phenotype (M2-like) is critical to successful infarct healing. Interventions that polarize macrophages towards an anti-inflammatory 'M2-like' phenotype improve infarct healing in the experimental MI mouse model and reduce subsequent adverse remodelling of the myocardium, but the endogenous mechanisms that regulate repair are not well understood. Furthermore, differences in the resolution of inflammation in C57BL/6 and BALB/c mice, which are two of the commonly used wild-type mouse strains in experimental MI have not been characterised. We previously found that low peripheral blood eosinophil count is associated with increased short-term risk of mortality in low-intermediate risk patients with ischaemic heart disease. This suggests that eosinophils may have a role in the successful remodelling and repair of the heart following myocardial infarction. Eosinophils express a number of immuno-modulating cytokines and lipid mediators implicated in the resolution of inflammation. Increasingly prominent is interleukin-4 (IL-4), a cytokine that has been found to maintain the anti-inflammatory M2-like phenotype in macrophages. We therefore hypothesised that IL-4Rα signalling and recruitment of eosinophils to the myocardium following infarction are key in regulating the subsequent inflammatory response and scar tissue formation during infarct repair and cardiac remodelling. Experimental MI was induced by permanent left anterior descending artery ligation in isofluorane anaesthetized 12-15 week-old male wild-type (WT) BALB/c, WT C57BL/6, IL4Rα-/-, IL-4Rαflox/-, IL-4Rαflox/-LysMCre mice and eosinophil-deficient ΔdblGATA mice. Cardiac function was characterised by high-resolution ultrasound and immune cell infiltration by flow cytometry of single cell infarct and remote zone tissue digests. Blood eosinophil count and 6-month all-cause mortality were assessed in 732 consecutive patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction (STEMI). The rate of mortality due to cardiac rupture was significantly higher in C57BL/6 mice in comparison with BALB/c mice at Day 7 post-MI. This was associated with a higher proportion of pro-inflammatory Ly-6Chi macrophages infiltrating the infarct zone tissue of C57BL/6 mice following MI. An accompanying reduction in the number of splenic Ly-6Chi monocytes post-MI, suggestive of splenic monocyte mobilisation, was seen in C57BL/6 mice but not found in BALB/c mice. Furthermore, C57BL/6 mice had a delayed transition in macrophage polarisation towards an anti-inflammatory phenotype. Disruption of IL4Rα signalling, in mice null for the IL4Rα gene, resulted in increased F4/80+ macrophage and pro-inflammatory Ly6Chi macrophage infiltration of the infarct zone and reduced expression of the anti-inflammatory macrophage marker CD206, compared to wild-type controls. Furthermore, expression of GATA3 and ST2, both associated with the immunosuppressive function of (CD4+ Foxp3+) regulatory T cells, was reduced in infarct zone regulatory T cells from IL4Rα-/- mice. These findings were associated with defective wound healing with impaired angiogenesis, increased scar size, disarrayed infarct zone collagen deposition, accompanied by modified expression of plod2 that encodes the collagen cross-linking enzyme lysyl hydroxylase 2. Resulting in greater left ventricular dilatation and loss of cardiac function, as well as a higher 7- day mortality due to cardiac rupture in IL4Rα-/- mice. This indicates that successful infarct repair requires the engagement of IL-4Rα signalling to facilitate the accumulation of anti-inflammatory macrophages and highly immunosuppressive ST2+ regulatory T cells in the heart following MI. Resident cardiac macrophages from naïve hearts of IL-4Rαflox/-LysMCre mice failed to undergo LysMCre-mediated deletion of the IL-4Rα gene, potentially because low or absent expression of Lyz2 (encoding lysozyme M). In both ST-elevation MI (STEMI) patients and mice after acute MI, there was a decline in peripheral blood eosinophil count, with activated eosinophils being recruited to the infarct zone and paracardial adipose tissue of mice. The transcription factors GATA-1 plays a role in the differentiation of eosinophils from eosinophil progenitor cells. Deletion of GATA-1 results in loss of the eosinophil lineage and has been exploited to develop the eosinophil-deficient ΔdblGATA mouse. ΔdblGATA mice were used to address the role of eosinophils in cardiac remodelling following MI. ΔdblGATA mice had increased left ventricular dilatation and reduced ejection fraction after induction of MI, relative to wild-type mice. ΔdblGATA mice had increased scar size with disarrayed infarct zone collagen deposition, accompanied by modified expression of the genes plod2 and lox, which are associated with collagen cross-linking. The proportion of CD206+ anti-inflammatory macrophages was less in the infarct zone of ΔdblGATA mice, but was restored by adoptive transfer of eosinophils from WT mice. Furthermore, adverse cardiac remodelling in eosinophil-deficient ΔdblGATA mice was rescued by provision of IL-4 complex following MI. In conclusion, an enhanced inflammatory response following MI underlies the increased risk of cardiac rupture seen with WT C57BL/6 mice in comparison to WT BALB/c mice. WT BALB/c mice are protected from cardiac rupture, which was associated with an absence of splenic monocyte mobilisation following ischaemic injury. The resolution of inflammation was found to be dependent on IL4Rα signalling which is crucial for cardiac repair and remodelling, through modulating inflammatory cell recruitment and phenotype, as well as scar formation. Eosinophils are recruited to the heart post-MI and are essential for regulating cardiac repair and remodelling, likely through provision of IL-4. Therefore, we were able to show that IL-4Rα signalling and recruitment of eosinophils to the myocardium following infarction are both key in regulating the subsequent inflammatory response and scar tissue formation during infarct healing and cardiac remodelling.

Elevated levels of reactive oxygen species (ROS) cause or aggravate a variety of pathological conditions such as cardiovascular disease, cancer and rheumatoid arthritis. Despite known links between oxidative stress and disease, years of clinical studies have failed to show clear benefits of antioxidant therapy. It is now recognized that ROS such as hydrogen peroxide can act as signaling molecules and are required for physiological functioning of a number of signaling pathways. Therefore, a mechanistic basis of ROS-mediated regulation of cell signaling must be established to enable rational design of antioxidant-based therapies. The challenges in quantification of transient changes mediated by ROS during cell signaling have impeded investigation of redox-regulated signaling. In the present work, computational modeling is used to circumvent these technical challenges and to test competing hypotheses of redox regulation. Using a quantitative, systems level approach to study interactions between ROS dependent and independent regulatory mechanisms, the most comprehensive model of the IL-4 signaling pathway to date has been developed and validated with experimental data. The model is capable of predicting kinase phosphorylation dynamics under new oxidative conditions, and our analyses suggest that reversible oxidation of tyrosine phosphatases is the primary mechanism of redox regulation in this pathway. Additional computational methods have been developed to study ROS as mediators of crosstalk between signaling pathways, to optimize model parameters, and to interrogate model dynamics for the purpose of model selection. Collectively, these modeling tools provide a new systems-level perspective for investigating reversible protein oxidation as a means of control over cellular signal transduction.

In 2015, American Heart Association (AHA) reported that 1 in 9 deaths are attributed to Heart failure (HF), the number one killer in the world. While advancements in interventional cardiology in conjunction with pharmacotherapies have significantly reduced the rate of mortality following MI, there has been a corresponding rise in chronic heart failure (CHF) in surviving patients, largely attributed to the limited regenerative capacity of the heart and the inadequate healing response. Myocardial ischemic injury triggers an exuberant local and systemic inflammation, and the extent and quality of the cardiac wound healing process is intricately tied to the delicate equilibrium of this inflammatory response. While cardiac regeneration is an important goal, it is imperative in the meantime to explore therapeutic strategies that target these inflammatory mediators of early cardiac repair. These interventions to influence and improve cardiac wound healing can represent a new therapeutic window to halt the progression of heart failure between the few hours that may be used to limit infarct size by reperfusion and an irreversible non-contractile cardiac scar. This dissertation examines three therapeutic delivery strategies aimed at modulating the immune response to enhance cardiac repair in rodent models MI: 1) Polyketal nanoparticles as siRNA delivery vehicles for antioxidant therapy; 2) Spherical nucleic acid particles for anti-inflammatory therapy and; 3) Bioactive PEG (polyethyleneglycol)-based hydrogel for immunomodulation. The work presented here applies novel nucleic acid delivery strategies for cardiac gene silencing and has contributed to new knowledge with regard to modulating the immune response following MI.

Background: IL-4 and IL-13 are related cytokines with similar functional properties. Differential regulation of IL-4 and IL-13 has not been described. Objective: We have examined the effects of IFN-α on antigen-driven proliferation, IL-4 generation, and IL-13 generation from human PBMCs and T-cell clones. Methods: Proliferation was assessed by 3H-thymidine incorporation. Cytokine generation was assessed by reverse transcription PCR and ELISA. Messenger RNA stability was assessed in the presence of actinomycin D. Results: IFN-α induced a concentration-dependent inhibition of antigen-driven proliferation of TH1 and TH2 clones (median effective concentration, 150 to 200 U/mL); the sensitivity of TH1 and TH2 clones to IFN-α was not significantly different (P = .6). IFN-α induced an analogous concentration-dependent inhibition of antigen-driven IL-13 generation from TH1 and TH2 clones (median effective concentration, 100 U/mL); this effect was evident by 12 hours of culture and persisted beyond 48 hours. However, IL-4 generation from TH2 clones was insensitive to IFN-α at all concentrations and times tested (1 to 10,000 U/mL). A similar inhibitory effect of IFN-α on mitogen-driven proliferation and IL-13 generation from PBMCs was demonstrated; once again, IL-4 generation from PBMCs was insensitive to IFN-α. IL-13 mRNA stability was unaffected by IFN-α, suggesting transcriptional regulation. Conclusion: IFN-α differentially regulates antigen-stimulated IL-4 and IL-13 generation.

Ce travail de thèse vise à l’identification des voies de signalisation cellulaires responsables de la régulation de l’expression des gènes humains DUOX dans la thyroïde. Les protéines DUOX1 et DUOX2 sont exprimées à la membrane apicale du thyrocyte, grâce à leur facteur de maturation DUOXA, et participent à la synthèse des hormones thyroïdiennes à travers la génération de peroxyde d’hydrogène. Les voies de signalisation et les facteurs de transcription contrôlant l’expression des gènes DUOX ne sont pas clairement définis dans les thyroïdes humaines et murines mais plusieurs études ont démontré une augmentation de leur expression via des cytokines inflammatoires dans des lignées cellulaires humaines. L’existence de cytokines susceptibles de réguler positivement l’expression des DUOX dans les thyrocytes a grandement suscité notre intérêt. En effet, il importe de comprendre les mécanismes responsables de leur expression car les protéines DUOX sont de plus en plus associées à des cancers et des maladies inflammatoires chroniques. Dans ce travail de recherche, il a été mis en évidence que les cytokines de type Th2 interleukine-4 et interleukine-13 augmentent la production de peroxyde d’hydrogène dans les thyrocytes humains en culture primaire suite à une induction des protéines DUOX2 et DUOXA2. L’interleukine-4 augmente aussi l’expression des couples de gènes Duox1/Duoxa1 et Duox2/Duoxa2 dans les thyrocytes murins, générant ainsi plus de peroxyde d’hydrogène. La stimulation par l’interleukine-4 et l’interleukine-13 dans les thyrocytes humains est dépendante du récepteur IL4RII et de l’activation de la voie de signalisation JAK1/STAT6. L’effet de l’interleukine-4 est contrecarré par la cytokine de type Th1 interféron-ɣ et est associée à une augmentation de l’expression de la protéine SOCS-1 qui bloque la fonction du facteur de transcription STAT6. L’induction de l’expression des gènes DUOX2/DUOXA2 dans des thyroïdes provenant de patients atteints de la maladie de Graves où le taux d’interleukine-4 sérique est susceptible d’être augmenté n’a pas pu être mise en évidence.In vitro, la mise en culture primaire affecte l’état de différenciation des thyrocytes murins ;en effet l’expression des marqueurs de la fonction thyroïdienne Nis, Tpo, Duox2 et Duoxa2 est diminuée, ce qui n’est pas le cas pour les gènes Duox1 et Duoxa1. Nous avons alors été convaincus de poursuivre l’étude de la régulation des Duox dans un système in vivo. Nous avons généré une nouvelle souris transgénique Thyr-IL-4, dans la souche C57BL/6J, surexprimant spécifiquement l’interleukine-4 dans la thyroïde. Deux lignées indépendantes de souris transgéniques ont été analysées. La souris Thyr-IL-4 a un phénotype euthyroïdien bien que la morphologie de ses follicules thyroïdiens soit altérée par une augmentation inattendue de leur taille. L’analyse du profil d’expression des gènes montre une forte induction de Duox1, Duoxa1 et Slc26a4 (Pendrine) dans les thyroïdes transgéniques ;il n’y a pas de modification de l’expression des gènes Duox2 et Duoxa2, tandis que l’expression du marqueur thyroïdien Slc5a5 (Nis) est diminuée. La surexpression de Duox1 est liée à une augmentation de la production de peroxyde d’hydrogène dans les tissus thyroïdiens transgéniques ex vivo, sans engendrer de dégâts cellulaires in vivo. Nous montrons pour la première fois la régulation de l’expression du gène et de la protéine Pendrine par l’interleukine-4 dans la thyroïde. La diminution de l’expression de Nis est associée à une diminution de captation de l’iode par les thyrocytes et du taux de thyroglobuline liée aux hormones thyroïdiennes T3 et T4 dans les thyroïdes transgéniques. Ces modifications d’expression de marqueurs thyroïdiens n’induisent pas un phénotype hypothyroïdien mais les souris jeunes Thyr-IL-4 sont plus susceptibles que les souris sauvages à développer une hypothyroïdie lorsqu’elles sont carencées en iode. Enfin nous n’observons pas d’infiltration leucocytaire majeure chez nos souris, pourtant l’expression de gènes impliqués dans des voies de signalisation immunitaires est augmentée. Suite à l’induction d’une réaction immunitaire dirigée contre le récepteur de la TSH, nous avons observé une réponse inflammatoire plus marquée dans les souris Thyr-IL-4 par rapport aux souris sauvages caractérisée par une infiltration leucocytaire CD45+ plus importante. / Doctorat en Sciences biomédicales et pharmaceutiques (Médecine) / info:eu-repo/semantics/nonPublished

No description available.

No description available.

No description available.

A rinossinusite crônica (RSC) é uma doença inflamatória da mucosa nasal, e pouco tem sido relacionada à exposição no ambiente de trabalho, em especial ao algodão. Atualmente, uma série de citocinas e quimiocinas tem sido estudada para elucidação das características imunológicas que levam ao desenvolvimento da doença. Objetivos: Caracterizar a exposição ao algodão como indutora de RSC e determinar o padrão de resposta inflamatória imuno-histoquímica da mucosa nasal de indivíduos expostos ou não ao algodão e que desenvolveram RSC. Casuística e Metodos: Por meio de questionário baseado no EPOS e SNOT-22 foi realizado diagnóstico clínico de RSC em indivíduos expostos ao algodão no ambiente de trabalho. Após a confirmação diagnóstica com tomografia computadorizada e nasofibroscopia flexível foi realizada biópsia na mucosa de concha média de pacientes com diagnóstico clínico de RSC para análise da expressão de IL-4, IL-5, IL-10, IL-17 e IL-33. A análise foi realizada também em grupo com RSC sem exposição ao algodão e controle sem RSC. Resultados: Todos os indivíduos expostos ao algodão com sintomatologia sugestiva de RSC apresentaram padrão histológico com aumento da expressão de IL-4, IL-5, IL-10, IL-17 e IL-33. Conclusões: O presente estudo comprovou a estreita relação entre a exposição ao algodão no ambiente de trabalho e o surgimento de uma resposta inflamatória com aumento da expressão das interleucinas estudadas. A possível instituição de terapias/medicamentos que inibissem a expressão dessas citocinas poderia auxiliar na diminuição do processo inflamatório presente na RSC e/ou no desencadeamento da doença / The chronic rhinusinusitis (CRS) is an inflammatory disease of the nasal mucosa, and has been little related to exposure in the work environment, especially to cotton. Currently, a number of cytokines and chemokines have been studied to elucidate the immunological characteristics that lead to the development of the disease. Objectives: To characterize exposure to cotton as an inducer of CRS and to determine the pattern of inflammatory immune-histochemical response of the nasal mucosa of individuals exposed or not to cotton and who developed CRS. Casuistic and Methods: Using a questionnaire based on EPOS and SNOT-22, a clinical diagnosis of CRS was performed in individuals exposed to cotton in the work environment. After diagnostic confirmation with computed tomography and flexible nasofibroscopy, biopsy was performed on the middle concha mucosa of patients with clinical diagnosis of CRS to analyze the expression of IL-4, IL-5, IL-10, IL-17 and IL- 33. The analysis was also performed in a group with CRS without exposure to cotton and control without CRS. Results: All individuals exposed to cotton with symptoms suggestive of CRS had a histological pattern with increased expression of IL-4, IL-5, IL-10, IL-17 and IL-33. Conclusions: This study confirms the close relationship between exposure to cotton in the workplace and the appearance of an inflammatory response with increased expression of interleukins studied. The possible institution of therapies / drugs that inhibit the expression of these cytokines could help in the reduction of the inflammatory process present in CRS and in the onset of the disease