Toll-like receptor 2/MyD88 signaling mediates zymosan-induced joint hypernociception in mice: Participation of TNF-alpha, IL-1 beta and CXCL1/KC

Arthritic pain is a serious health problem that affects a large number of patients. Toll-like receptors (TLRs) activation within the joints has been implicated in pathophysiology of arthritis. However, their role in the genesis of arthritic pain needs to be demonstrated. In the present study, it was addressed the participation of TLR2 and TLR4 and their adaptor molecule MyD88 in the genesis of joint hypernociception (a decrease in the nociceptive threshold) during zymosan-induced arthritis. Zymosan injected in the tibio-tarsal joint induced mechanical hypernociception in C57BL/6 wild type mice that was reduced in TLR2 and MyD88 null mice. On the other hand, zymosan-induced hypernociception was similar in C3H/HePas and C3H/Hej mice (TLR4 mutant mice). Zymosan-induced joint hypernociception was also reduced in TNFR1 null mice and in mice treated with IL-1 receptor antagonist or with an antagonist of CXCR1/2. Moreover, the joint production of TNF-alpha, IL-1 beta and CXCL1/KC by zymosan was dependent on TLR2/MyD88 signaling. Investigating the mechanisms by which TNF-alpha, IL-1 beta and CXCL1/KC mediate joint hypernociception, joint administration of these cytokines produced mechanical hypernociception, and they act in an interdependent manner. In last instance, their hypernociceptive effects were dependent on the production of hypernociceptive mediators, prostaglandins and sympathetic amines. These results indicate that in zymosan-induced experimental arthritis, TLR2/MyD88 is involved in the cascade of events of joint hypernociception through a mechanism dependent on cytokines and chemokines production. Thus, TLR2/MyD88 signaling might be a target for the development of novel drugs to control pain in arthritis. (C) 2011 Elsevier B.V. All rights reserved.

Differential inflammasome expression and IL-1β secretion in monocyte-derived dendritic cells differentiated with IL-4 or IFN-α

NLRP3-inflammasome activation was evaluated in monocyte-derived dendritic cells (DC) obtained through IL-4 (IL4-DC) or IFN-α (IFN-DC) protocols and pulsed with chemically inactivated HIV-1. Inflammasome' genes expression and IL-1β secretion were compared in DC isolated from 15 healthy subjects (HC) and 10 HIV-1 infected individuals (HIV+). FINDINGS: Whether HIV was able to increased NLRP3-inflammasome genes expression and IL-1β secretion in IL4-DC from HC, the induction of inflammasome appeared significantly reduced in IFN-DC from HC, suggesting a different responsive state of IFN-DC compared to IL4-DC. No inflammasome activation was observed in IL4-DC as well as in IFN-DC derived from HIV + subjects, confirming previous findings on "unresponsive" state of DC derived from HIV + possibly due to chronic inflammatory state of these individuals. CONCLUSIONS: Our results showed that IFN-α differently modulates inflammasome expression during monocytes-DC in vitro differentiation. These findings could be of interest considering the on-going research about DC manipulation and therapeutic strategies for HIV + involving DC-based immune-vaccines.

Interleukin-10 production by tumor infiltrating macrophages plays a role in Human Papillomavirus 16 tumor growth

Abstract Background Human Papillomavirus, HPV, is the main etiological factor for cervical cancer. Different studies show that in women infected with HPV there is a positive correlation between lesion grade and number of infiltrating macrophages, as well as with IL-10 higher expression. Using a HPV16 associated tumor model in mice, TC-1, our laboratory has demonstrated that tumor infiltrating macrophages are M2-like, induce T cell regulatory phenotype and play an important role in tumor growth. M2 macrophages secrete several cytokines, among them IL-10, which has been shown to play a role in T cell suppression by tumor macrophages in other tumor models. In this work, we sought to establish if IL-10 is part of the mechanism by which HPV tumor associated macrophages induce T cell regulatory phenotype, inhibiting anti-tumor activity and facilitating tumor growth. Results TC-1 tumor cells do not express or respond to IL-10, but recruit leukocytes which, within the tumor environment, produce this cytokine. Using IL-10 deficient mice or blocking IL-10 signaling with neutralizing antibodies, we observed a significant reduction in tumor growth, an increase in tumor infiltration by HPV16 E7 specific CD8 lymphocytes, including a population positive for Granzyme B and Perforin expression, and a decrease in the percentage of HPV specific regulatory T cells in the lymph nodes. Conclusions Our data shows that in the HPV16 TC-1 tumor mouse model, IL-10 produced by tumor macrophages induce regulatory phenotype on T cells, an immune escape mechanism that facilitates tumor growth. Our results point to a possible mechanism behind the epidemiologic data that correlates higher IL-10 expression with risk of cervical cancer development in HPV infected women.

O edifício da FAUUSP e os materiais do brutalismo

O trabalho analisa a história da produção do edifício da Faculdade de Arquitetura e Urbanismo da Universidade de São Paulo, projetado por João Batista Vilanova Artigas (1915-1985) em 1961 e concluído em 1969. Mais especificamente, o artigo se volta aos materiais do edifício, oferecendo insumos para uma discussão sobre o papel do chamado “brutalismo paulista” na década de 1960. O edifício da FAUUSP, como se sabe, é um marco na arquitetura moderna brasileira. Seu caráter paradigmático consiste na síntese das posições programáticas de Artigas, tanto em relação ao ensino de arquitetura como em relação à poética moderna, que ultrapassa o limite autoral e constitui uma escola. São características dessa escola – por vezes chamada de “paulista”, “brutalista” ou “artiguista” – alguns princípios como a continuidade espacial, o elogio das formas estruturais, a verdade dos materiais e o desenvolvimento das forças produtivas através da superação tecnológica. Esses princípios respondiam a algumas das questões mais urgentes da arquitetura moderna brasileira naquele período, deslocando a nova monumentalidade para uma dimensão construtiva. A nova poética, claramente exposta no projeto da FAUUSP, coincide com o surgimento de uma estética que atribuiu um novo valor político e crítico à produção. Passam a ser frequentes, por exemplo, interpretações do concreto armado brasileiro como síntese do subdesenvolvimento, por suas marcas de feitura artesanal e seus recordes tecnológicos. O objetivo deste artigo é contribuir com esse debate caracterizando em detalhe a produção do edifício em seus materiais: o concreto armado, a esquadria, os materiais de acabamento e os componentes industriais. O exame de aspectos históricos da produção do edifício, recolhidos em documentos originais e depoimentos, permite verificarmos de que modo a poética arquitetônica participa das decisões da obra e qual o seu impacto na economia do edifício e em sua forma de produção. Aprendemos, por exemplo, que o concreto armado apresenta manifestações visuais distintas e independentes de seu modo de produção (que foram pelo menos três: moldado in loco, protendido, e com agregados leves, sem função estrutural); que a empena da fachada exigiu uma fundação própria para seu cimbramento; que a modulação dos caixilhos não correspondia à modulação da estrutura; que a resina epóxi foi usada de modo pioneiro e experimental; que as fôrmas foram produzidas por um hábil carpinteiro português, mas as relações de trabalho eram precárias; que a contratação do projeto básico previa o detalhamento durante a obra pelo Escritório Técnico do Fundo para a Construção da Cidade Universitária. Essa noção ampla de material, entendida como a matéria mais o trabalho social que a define historicamente, nos permite tratar, simultaneamente, de aspectos técnicos, econômicos e artísticos da obra e assim compreender com maior exatidão dos termos do debate acerca da produção na arquitetura “brutalista” e seu papel político.

J/psi production as a function of charged particle multiplicity in pp collisions at root s=7 TeV

The ALICE Collaboration reports the measurement of the relative J/psi yield as a function of charged particle pseudorapidity density dN(ch)/d eta in pp collisions at root s = 7 TeV at the LHC. J/psi particles are detected for p(t) > 0, in the rapidity interval vertical bar y vertical bar < 0.9 via decay into e(+)e(-), and in the interval 2.5 < y < 4.0 via decay into mu(+)/mu(-) pairs. An approximately linear increase of the J/psi yields normalized to their event average (dN(J/psi)/dy)/(dN(J/psi)/dy) with (dN(ch)/c eta)/(dN(ch)/d eta) is observed in both rapidity ranges, where dN(ch)/d eta is measured within vertical bar eta vertical bar < 1 and p(t) > 0. In the highest multiplicity interval with (dN(ch)/d eta)(bin)) = 24.1, corresponding to four times the minimum bias multiplicity density, an enhancement relative to the minimum bias J/psi yield by a factor of about 5 at 2.5 < y <4 (8 at vertical bar y vertical bar < 0.9) is observed. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.