RESUMO
Toxoplasma gondii (T. gondii) is an intracellular parasite responsible for causing toxoplasmosis. When infection occurs during pregnancy, it can produce severe congenital infection with ocular and neurologic damage to the infant. From the oral infection parasite reaches the intestine, causing inflammatory response, damage in tissue architecture and systemic dissemination. Macrophage migration inhibition factor (MIF) is a cytokine secreted from both immune and non-immune cells, including gut epithelial cells. MIF is described to promote inflammatory responses, to be associated in colitis pathogenesis and also to play role in maintaining the intestinal barrier. The aim of the present study was to evaluate the influence of the pregnancy and MIF deficiency on T. gondii infection in the intestinal microenvironment and to address how these factors can impact on the intestinal architecture and local cytokine profile. For this purpose, small intestine of pregnant and non-pregnant C57BL/6 MIF deficient mice (MIF-/-) and Wild-type (WT) orally infected with 5 cysts of ME-49 strain of T. gondii were collected on day 8th of infection. Intestines were processed for morphological and morphometric analyses, parasite quantification and for cytokines mensuration. Our results showed that the absence of MIF and pregnancy caused an increase in T. gondii infection index. T. gondii immunolocalization demonstrated that segments preferentially infected with T. gondii were duodenum and ileum. The infection caused a reduction in the size of the intestinal villi, whereas, infection associated with pregnancy caused an increase in villi size due to edema caused by the infection. Also, the goblet cell number was increased in the ileum of MIF-/- mice, when compared to the corresponding WT group. Analyses of cytokine production in the small intestine showed that MIF was up regulated in the gut of pregnant WT mice due to infection. Also, infection provoked an intense Th1 response that was more exacerbated in pregnant MIF-/- mice. We also detected that the Th2/Treg response was more pronounced in MIF-/- mice. Altogether, our results demonstrated that pregnancy and MIF deficiency interferes in the balance of the intestinal cytokines and favors a Th1-immflamatory profile, which in turn, impact in the development of pathology caused by T. gondii infection in the intestinal microenvironment.
Assuntos
Duodeno/imunologia , Íleo/imunologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Complicações Parasitárias na Gravidez/imunologia , Toxoplasma/imunologia , Toxoplasmose/imunologia , Animais , Feminino , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos , Camundongos Knockout , Gravidez , Complicações Parasitárias na Gravidez/genética , Toxoplasmose/genéticaRESUMO
Human macrophage migration inhibition factor (MIF) is a protein with cytokine and chemokine properties that regulates a diverse range of physiological functions related to innate immunity and inflammation. Most research has focused on the role of MIF in different inflammatory diseases. D-dopachrome tautomerase (DDT), a different molecule with structural similarities to MIF, which shares receptors and biological functions, has recently been reported, but little is known about its roles and mechanisms. In this review, we sought to understand the similarities and differences between these molecules by summarizing what is known about their different structures, receptors and mechanisms regulating their expression and biological activities with an emphasis on immunological aspects.
Assuntos
Fatores Imunológicos/imunologia , Imunomodulação/imunologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Animais , HumanosRESUMO
Chronic periodontitis (CP) is an infection that affects the teeth supporting structure. Macrophage migration inhibitory factor (MIF) is an important effector cytokine of the innate immune system. Due to its functional characteristics, MIF may be involved in the immunopathology of CP. The aim of the present study was to evaluate MIF levels in gingival crevicular fluid (GCF), saliva, and serum of CP patients. A cross-sectional study was conducted on 60 subjects divided into two groups: subjects with CP (n= 30) and periodontally healthy subjects without CP (n=30). MIF was quantified in GCF, saliva, and serum of all participants by enzyme-linked immunosorbent assay. MIF concentrations were higher in GCF, saliva, and serum in the group with CP compared with the group without CP and a higher MIF concentration was observed in GCF (p=0.001) and saliva (p=0.009) in the group with CP. MIF intragroup comparisons between fluids demonstrated significant high levels of MIF in saliva compared with GCF and serum in both study groups (p<0.05). A positive correlation was found between clinical signs and MIF concentration in GCF (p<0.05). There is an association between the MIF and the clinical signs of the disease. Therefore, MIF could have an important role in the pathology and progression of CP.
Assuntos
Periodontite Crônica/genética , Periodontite Crônica/metabolismo , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Adulto , Periodontite Crônica/sangue , Periodontite Crônica/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Líquido do Sulco Gengival/imunologia , Líquido do Sulco Gengival/metabolismo , Humanos , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/química , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Pessoa de Meia-Idade , Saliva/imunologia , Saliva/metabolismoRESUMO
Leprosy is a chronic disease caused by Mycobacterium leprae that affects the skin and peripheral nerves. It may present as one of two distinct poles: the self-limiting tuberculoid leprosy and the highly infectious lepromatous leprosy (LL) characterized by M. leprae-specific absence of cellular immune response. The pro-inflammatory cytokine macrophage migration inhibitory factor (MIF) enhance the bactericide activities of macrophages after interaction with its receptor, CD74. Importantly, MIF also possesses chemoattractant properties, and it is a key factor in situ for the activation of macrophages and in blood to promote leukocytes migration. MIF-mediated activation of macrophages is a key process for the elimination of pathogens such as Mycobacterium tuberculosis; however, its participation for the clearance of M. leprae is unclear. The aim of this study was to evaluate the serum levels of MIF as well as MIF and CD74 expression in skin lesions of LL and compare it with healthy skin (HSk) taken from subjects attending to dermatological consult. Samples of serum and skin biopsies were taken from 39 LL patients and compared with 36 serum samples of healthy subjects (HS) and 10 biopsies of HSk. Serum samples were analyzed by ELISA and skin biopsies by immunohistochemistry (IHC). IHC smears were observed in 12 100× microscopic fields, in which percentage of stained cells and staining intensity were evaluated. Both variables were used to calculate a semi-quantitative expression score that ranged from 0 to 3+. We found no differences in MIF levels between LL patients and HS in sera. In addition, MIF was observed in over 75% of cells with high intensity in the skin of patients and HSk. Although we found no differences in MIF expression between the groups, a CD74 score statistically higher was found in LL skin than HSk (p < 0.001); this was the result of a higher percentage of cells positive for CD74 (p < 0.001). As a conclusion, we found that CD74-positive cells are intensely recruited to the skin with LL lesions. In this manner, MIF signaling may be enhanced in the skin of LL patients due to increased expression of its receptor, but further studies are required.
Assuntos
Antígenos de Diferenciação de Linfócitos B/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Oxirredutases Intramoleculares/sangue , Hanseníase Virchowiana/imunologia , Fatores Inibidores da Migração de Macrófagos/sangue , Pele/imunologia , Adulto , Antígenos de Diferenciação de Linfócitos B/metabolismo , Biópsia , Estudos de Casos e Controles , Feminino , Voluntários Saudáveis , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunidade Celular , Oxirredutases Intramoleculares/imunologia , Oxirredutases Intramoleculares/metabolismo , Hanseníase Virchowiana/sangue , Hanseníase Virchowiana/patologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Mycobacterium leprae/imunologia , Pele/citologia , Pele/patologiaRESUMO
Macrophage migration Inhibitory Factor (MIF) is a cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive-feedback-loop with proinflammatory cytokines and could perpetuate the inflammatory process in Systemic Lupus Erythematosus (SLE).The aim of this study was to assess the effect of recombinant-human-MIF (rhMIF) on the expression of Th1, Th2 and Th17 cytokines in Peripheral Blood Mononuclear Cells (PBMC) from Healthy Subjects (HS) and SLE patients. The PBMC were isolated from SLE patients classified according to the 1997 SLE ACR criteria and HS donors; all subjects included were women from an unrelated Mexican-Mestizo population. The PBMC isolated were stimulated with rhMIF, LPS and ISO-1 in different combinations; Th1, Th2 and Th17cytokine profiles levels were determined by MAGPIX Bio-plex assay in supernatants from cell cultures. We observed in supernatants of PBMCs from HS treated with rhMIF a predominance of Th17 cytokine profile with an increase of IL-17A, IL-17F and IL-21 versus PBMCs from SLE patients, which showed an inflammatory profile represented by increase of IL-6 cytokine. According to SLE remission/activity presented at enrollment in the study (Mex-SLEDAI index), the PBMC from active SLE patients showed higher levels of TNF-α and IL-6 versus PBMC from remission SLE patients. In conclusion, our results suggest that MIF can induce a differential inflammatory response in physiological and pathological conditions with a predominance of a Th17 cytokine profile in PBMC from HS and an increase in TNF-α and IL-6 expression in PBMC from active SLE patients.
Assuntos
Interleucina-6/imunologia , Oxirredutases Intramoleculares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Estudos de Casos e Controles , Citocinas/imunologia , Feminino , Humanos , Interleucina-17/imunologia , Interleucina-6/sangue , Oxirredutases Intramoleculares/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Lúpus Eritematoso Sistêmico/sangue , Fatores Inibidores da Migração de Macrófagos/farmacologia , Pessoa de Meia-Idade , Cultura Primária de Células , Proteínas Recombinantes/farmacologia , Células Th1/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Fator de Necrose Tumoral alfa/sangueRESUMO
Macrophage migration inhibitory factor (Mif) is highly expressed in type 1 diabetes mellitus (T1DM). However, there is limited information about how Mif influences the activation of macrophages (Mφ) and dendritic cells (DC) in T1DM. To address this issue, we induced T1DM by administering multiple low doses of streptozotocin (STZ) to Mif-/- or wild-type (Wt) BALB/c mice. We found that Mif-/- mice treated with STZ (Mif-/-STZ) developed lower levels of hyperglycemia, inflammatory cytokines, and specific pancreatic islet antigen- (PIAg-) IgG and displayed reduced cellular infiltration into the pancreatic islets compared to Wt mice treated with STZ (WtSTZ). Moreover, Mφ and DC from Mif-/-STZ displayed lower expression of MHC-II, costimulatory molecules CD80, CD86, and CD40, Toll-like receptor- (TLR-) 2, and TLR-4 than WtSTZ. These changes were associated with a reduced capacity of Mφ and DC from Mif-/-STZ to induce proliferation in ovalbumin-specific T cells. All the deficiencies observed in Mif-/-STZ were recovered by exogenous administration of recombinant Mif. These findings suggest that Mif plays a role in the molecular mechanisms of Mφ and DC activation and drives T cell responses involved in the pathology of T1DM. Therefore, Mif is a potential therapeutic target to reduce the pathology of T1DM.
Assuntos
Células Dendríticas/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 1/imunologia , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Macrófagos/imunologia , Células Th1/imunologia , Animais , Autoanticorpos/imunologia , Antígeno B7-1/imunologia , Antígeno B7-2/imunologia , Glicemia/metabolismo , Antígenos CD40/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Imunoglobulina G , Interferon gama/imunologia , Oxirredutases Intramoleculares/imunologia , Ilhotas Pancreáticas/patologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Índice de Gravidade de Doença , Receptor 2 Toll-Like/imunologia , Receptor 4 Toll-Like/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Dengue fever is usually a benign acute viral infection transmitted by arthropods but may evolve to severe clinical manifestations such as coagulation and/or hemodynamic disorders, caused mainly by an increase of vascular permeability. Deregulated circulating immunological factors have been associated with severity. In Brazil severe cases appeared in children only recently and we evaluated the profile of cytokine/chemokine kinetics in 134 hospitalized young patients during the epidemic in Rio de Janeiro in 2008. Inflammatory cytokines TNF and IFNγ were found elevated during the acute phase in children as well as the anti-inflammatory IL10 and chemokines MIF and CXCL10/IP10, all last three persisting longer during the recovery phase. Severe disease fitting the dengue hemorrhagic fever pattern (WHO, 1997) was associated with higher IL10 and CXCL10/IP10 circulating levels (peak levels at seven days with P<0.01 and P<0.001 respectively as compared to DF). These factors were higher in patients pulmonary effusion or ascites (P<0.05 for IL10 and P<0.01 for CXCL10/IP10). Both factors were also associated with liver changes such as AST increase correlated with CXCL10/IP10 (r=0.4300 with P<0.0001) and patients presenting painful hepatomegaly showed higher circulating levels of IL10 (P<0.01, at 7-9 days) and of CXCL10/IP10 (P<0.05, 4-6 days and P<0.001, 7-9 days) when compared to patients without apparent liver alterations. Most cases presented a history of prior infection (93%). This is the first study demonstrating cytokine and chemokine association with severity during dengue fever in Brazilian children. IL10 and CXCL10/IP10 play a role in the disease severity associated with induction of vascular leakage and a novel association with changes in liver dysfunction.
Assuntos
Permeabilidade Capilar/imunologia , Quimiocinas/imunologia , Epidemias , Hepatopatias/imunologia , Dengue Grave/imunologia , Doença Aguda , Adolescente , Alanina Transaminase/metabolismo , Ascite/etiologia , Ascite/imunologia , Aspartato Aminotransferases/metabolismo , Brasil/epidemiologia , Quimiocina CXCL10/imunologia , Criança , Pré-Escolar , Estudos de Coortes , Citocinas/imunologia , Dengue/complicações , Dengue/epidemiologia , Dengue/imunologia , Feminino , Hepatomegalia/etiologia , Hepatomegalia/imunologia , Humanos , Lactente , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-13/imunologia , Oxirredutases Intramoleculares/imunologia , Hepatopatias/etiologia , Hepatopatias/metabolismo , Fatores Inibidores da Migração de Macrófagos/imunologia , Masculino , Derrame Pleural/etiologia , Derrame Pleural/imunologia , Estudos Retrospectivos , Dengue Grave/complicações , Dengue Grave/epidemiologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Macrophage migration inhibitory factor (MIF) is involved in eosinophil biology and in type 2 inflammation, contributing to allergic and helminthic diseases. We hypothesized that MIF participates in the pathogenesis of eosinophilic esophagitis (EoE), an allergic condition characterized by esophageal eosinophilic inflammation. MIF is highly expressed in esophageal mucosa of patients with EoE, compared with gastro-esophageal reflux disease and control patients, where it co-localizes predominantly with eosinophils. In vitro, recombinant MIF promotes human eosinophil chemotaxis, while MIF antagonist and CXCR4 antagonist, AMD3100, revert this effect. In a model of EoE induced by ovalbumin, Mif-deficient mice have reduced inflammation and collagen deposition compared with wild-type (WT) mice. Importantly, treatment of WT mice with anti-MIF or with AMD3100 during the challenge phase prevents accumulation of eosinophils and tissue remodeling. Conversely, recombinant MIF promoted tissue eosinophil inflammation in allergic mice. Together, these results implicate MIF in the pathogenesis of esophageal inflammation and suggest that targeting MIF might represent a novel therapy for EoE.
Assuntos
Esofagite Eosinofílica/imunologia , Eosinófilos/imunologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Adolescente , Adulto , Animais , Benzilaminas , Ciclamos , Esofagite Eosinofílica/genética , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/terapia , Eosinófilos/patologia , Feminino , Compostos Heterocíclicos/farmacologia , Humanos , Oxirredutases Intramoleculares/genética , Fatores Inibidores da Migração de Macrófagos/genética , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Mucosa/imunologia , Mucosa/patologia , Receptores CXCR4/antagonistas & inibidores , Receptores CXCR4/genética , Receptores CXCR4/imunologiaRESUMO
Deposition of immune complexes (IC) triggers Fc gamma R-dependent inflammation, leading to tissue damage in rheumatoid arthritis, systemic lupus erythematous, immune glomerulonephritis, and several immune vasculitides. Evidences support a role for macrophage migration inhibitory factor (MIF) in a number of inflammatory diseases, but the triggering of its secretion and its physiopathological role upon IC deposition remain elusive. Herein, we show that human macrophages secreted MIF after IC recognition, which in turn controlled the secretion of TNF. Macrophages from Mif-/- mice produced smaller amounts of TNF when stimulated with IgG-opsonized erythrocytes than wild-type (WT) cells. Using passive reverse Arthus reaction in the peritoneum and lungs as a model for IC-induced inflammation, we demonstrated that Mif-/- mice had a milder response, observed by reduced neutrophil recruitment, vascular leakage, and secretion of TNF, MIP-2, and keratinocyte-derived chemokine compared with WT controls. Adoptive transfer of alveolar macrophages from WT to Mif-/- mice rescued pulmonary neutrophil recruitment and TNF production upon passive reverse Arthus reaction. Our study indicates that Arthus inflammatory reaction is largely dependent on MIF and poses macrophages as a source of the MIF released upon IC recognition. These results give experimental support to the proposition that blockade of MIF might constitute an adjunctive, therapeutic approach to IC disease.
Assuntos
Reação de Arthus/imunologia , Inflamação/imunologia , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/imunologia , Macrófagos Alveolares/imunologia , Fatores de Necrose Tumoral/biossíntese , Transferência Adotiva , Animais , Complexo Antígeno-Anticorpo/imunologia , Células Cultivadas , Feminino , Humanos , Inflamação/patologia , Pulmão/imunologia , Macrófagos Alveolares/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose , Receptores de IgG/imunologiaRESUMO
Studies have demonstrated that oviductal fluid (ODF) proteins associate with eggs of numerous species including the bovine. In this study, the association of three ODF proteins, the bovine oestrus-associated protein, osteopontin (OPN), lipocalin-type prostaglandin D synthase (L-PGDS), with the bovine zona pellucida (ZP) was demonstrated by immunohistochemistry and western blot. The biological function of ODF derived egg-associated OPN and L-PGDS in sperm binding, fertilization and embryonic development was also explored. In vitro matured bovine oocytes were pre-incubated with ODF collected by cannula from cows in oestrus, or ODF with antibodies to OPN, L-PGDS and bovine serum albumin (BSA). Following incubation, oocytes were inseminated with 1 x 10(5) frozen-thawed spermatozoa, and they were evaluated for sperm binding, fertilization and embryonic development in vitro. Pre-treatment of ODF with antibodies to all of proteins reduced sperm binding to the ZP and fertilization in vitro. Cleavage rates were not significantly different among incubations, but rates of embryo development were significantly decreased. We conclude that antibodies to OPN, L-PGDS and BSA react with oocytes incubated with ODF and inhibit sperm binding, fertilization and embryonic development in vitro, suggesting a potential role of these proteins in these events.
Assuntos
Anticorpos/farmacologia , Bovinos/fisiologia , Fertilização/fisiologia , Oviductos/fisiologia , Interações Espermatozoide-Óvulo/fisiologia , Zona Pelúcida/metabolismo , Animais , Western Blotting/veterinária , Bovinos/embriologia , Feminino , Fertilização in vitro/efeitos dos fármacos , Fertilização in vitro/veterinária , Glicoproteínas/imunologia , Glicoproteínas/metabolismo , Imuno-Histoquímica/veterinária , Oxirredutases Intramoleculares/imunologia , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/imunologia , Lipocalinas/metabolismo , Masculino , Osteopontina/imunologia , Osteopontina/metabolismo , Gravidez , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Zona Pelúcida/fisiologiaRESUMO
The present study was conducted to determine the affect of pre-treating of oocytes and/or sperm with a rabbit polyclonal antibody against recombinant cattle lipocalin type prostaglandin D synthase (alpha L-PGDS) on in vitro sperm-oocyte binding and fertilization. In vitro matured cattle oocytes were incubated (39 degrees C, 5% CO(2) in air) for 1h in the following treatments either 500 microL of fertilization medium (FM) or FM with alpha L-PGDS (1:2000). Frozen-thawed spermatozoa were washed by a 45/90% layered Percoll gradient centrifugation and incubated for 1h either FM or FM with alpha L-PGDS. This study utilized five different treatments: (1) no antibody (control); (2) a rabbit IgG against a non-bovine antigen, bacterial histidase (alpha-hist); (3) alpha L-PGDS at fertilization time (with fertilization medium); (4) alpha L-PGDS-treated oocytes; or (5) alpha L-PGDS-treated sperm. Pre-treated oocytes were incubated with 10 x 10(4) washed spermatozoa per 25 oocytes. Oocytes used to assess sperm binding were stained with Hoescht 33342, and the number of sperm bound per zonae pellucidae counted. The remaining oocytes were fixed in acid alcohol, stained with 1% acetate-orcein and observed to determine the presence of pronuclei. More sperm bound to the zonae pellucidae when oocytes and/or sperm were pre-treated with alpha L-PGDS: (1) 26.4+/-3.0; (2) 25.6+/-3.0; (3) 59.7+/-3.0; (4) 56.4+/-3.0; and (5) 57.1+/-3.0. Addition of alpha L-PGDS with sperm, oocytes, or both, decreased fertilization (P<0.05) compared with the control: (1) 89.2+/-2.0%; (2) 87.5+/-2.0%; (3) 19.4+/-2.0%; (4) 27.2+/-3.1%; and (5) 14.1+/-3.4%. The alpha L-PGDS reacts with both oocytes and spermatozoa, resulting in increases of in vitro sperm-oocyte binding and inhibition of fertilization. These observations suggest that L-PGDS may have a role in cattle fertilization.
Assuntos
Anticorpos/farmacologia , Bovinos/fisiologia , Fertilização in vitro/veterinária , Oxirredutases Intramoleculares/imunologia , Lipocalinas/imunologia , Oócitos/efeitos dos fármacos , Interações Espermatozoide-Óvulo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Animais , Feminino , Fertilização in vitro/efeitos dos fármacos , Imunoglobulina G/farmacologia , Oxirredutases Intramoleculares/química , Oxirredutases Intramoleculares/fisiologia , Lipocalinas/química , Lipocalinas/fisiologia , Masculino , Fatores de TempoRESUMO
Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF(-/-) mice occurs regardless of high concentrations of IL-4 in the lung and OVA-specific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF(-/-) mice compared to WT, but were reduced in the spleen of MIF(-/-), thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4(+) cells with anti-CD3 antibody demonstrated that MIF(-/-) cells produced increased amounts of IFN-gamma and IL-4 compared to WT CD4(+) cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma.
Assuntos
Alérgenos/imunologia , Asma/metabolismo , Diferenciação Celular/imunologia , Oxirredutases Intramoleculares/fisiologia , Fatores Inibidores da Migração de Macrófagos/fisiologia , Células Th2/citologia , Animais , Asma/imunologia , Soros Imunes/administração & dosagem , Oxirredutases Intramoleculares/antagonistas & inibidores , Oxirredutases Intramoleculares/imunologia , Fatores Inibidores da Migração de Macrófagos/antagonistas & inibidores , Fatores Inibidores da Migração de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Muco/metabolismo , Células Th2/imunologia , Células Th2/metabolismoRESUMO
The involvement of jasmonates in the tuber development has been proved by the presence of many of these compounds in potato stolons, modification of their levels during the transition of the stolon into tuber, and induction of cell expansion upon exogenous jasmonates treatment. However, to date there is only little evidence of the presence of the jasmonic acid-biosynthetic enzymes in stolons or young tubers. As allene oxide cyclase represents the major control point for jasmonic acid biosynthesis, we studied the occurrence of allene oxide cyclase by immunological approaches in the early stages of tuber formation. In developing stolons, allene oxide cyclase as well as lipoxygenase were clearly detectable, but their levels did not change during development. Jasmonic acid treatment for 24h, however, increased lipoxygenase and allene oxide cyclase protein levels in both developmental stages analyzed. In longitudinal sections of stolons of stages 1 and 2, allene oxide cyclase and lipoxygenase occurred in the apex and along the stolon axis. Allene oxide cyclase was clearly detectable in epidermal, cortical and pith parenchymatic cells, showing the highest levels in vascular tissues surrounding cells. Lipoxygenase was mainly located in the parenchymatic cortex cells. The occurrence of allene oxide cyclase in stolons together with the previous identification of jasmonates from developing stolons reveals that these organs are capable to synthesize and metabolize jasmonates.