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IL-17D is a cytokine that belongs to the IL-17 family and is conserved in vertebrates and invertebrates. In contrast to IL-17A and IL-17F, which are expressed in Th17 cells, IL-17D is expressed broadly in nonimmune cells. IL-17D can promote immune responses to cancer and viruses in part by inducing chemokines and recruiting innate immune cells such as NK cells. Although bacterial infection can induce IL-17D in fish and invertebrates, the role of mammalian IL-17D in antibacterial immunity has not been established. To determine whether IL-17D has a role in mediating host defense against bacterial infections, we studied i.p. infection by group A Streptococcus (GAS) in wild-type (WT) and Il17d−/− mice. Compared with WT animals, mice deficient in IL-17D experienced decreased survival, had greater weight loss, and showed increased bacterial burden in the kidney and peritoneal cavity following GAS challenge. In WT animals, IL-17D transcript was induced by GAS infection and correlated to increased levels of chemokine CCL2 and greater neutrophil recruitment. Of note, GAS-mediated IL-17D induction in nonimmune cells required live bacteria, suggesting that processes beyond recognition of pathogen-associated molecular patterns were required for IL-17D induction. Based on our results, we propose a model in which nonimmune cells can discriminate between nonviable and viable GAS cells, responding only to the latter by inducing IL-17D.

Interleukin-17D (IL-17D) is a cytokine that belongs to the IL-17 family and is conserved in vertebrates and invertebrates. In contrast to IL-17A and IL-17F, which are expressed in Th-17 cells, IL-17D is expressed broadly in non-immune cells. IL-17D can promote immune responses to cancer and viruses in part by inducing chemokines and recruiting innate immune cells such as natural killer (NK) cells. Although bacterial infection can induce IL-17D in fish and invertebrates, the role of mammalian IL-17D in anti-bacterial immunity has not been established. To determine whether IL-17D has a role in mediating host defense against bacterial infections, we studied intraperitoneal infection by group A Streptococcus (GAS) in wild-type (WT) and Il17d(−/−) mice. Compared to WT animals, mice deficient in IL-17D experienced decreased survival, had greater weight loss, and showed increased bacterial burden in the kidney and peritoneal cavity following GAS challenge. In WT animals, IL-17D transcript was induced by GAS infection and correlated to increased levels of chemokine CCL2 and greater neutrophil recruitment. Of note, GAS-mediated IL-17D induction in non-immune cells required live bacteria, suggesting that processes beyond recognition of pathogen-associated molecular patterns were required for IL-17D induction. Based on our results, we propose a model in which non-immune cells can discriminate between non-viable and viable GAS cells, responding only to the latter by inducing IL-17D.

Objetivo: Relatar um caso de sepse em gestação pré-termo, ocorrido em um hospital de ensino e pesquisa, referência no atendimento à gestante de alto risco, no Estado do Pará. Detalhamento do caso: Paciente do sexo feminino, 26 anos, primigesta, portadora de Artrite Reumatoide, com Idade Gestacional de 32 semanas e 3 dias com queixa de lombalgia e dor em baixo ventre. O quadro evoluiu com polaciúria, Giordano positivo a direita, colo entreaberto e perda do tampão mucoso. No segundo dia de internação a paciente apresentou taquicardia e após a realização da ultrassonografia obstétrica foi constatado a morte fetal intrauterina. Após avaliação, e posterior piora do quadro, foi prescrito novo de antibiótico e mudança para leito em unidade de terapia intensiva, assim como a realização da interrupção cirúrgica da gravidez. Considerações finais: Visto à rápida evolução do quadro de sepse, e ao difícil diagnóstico do quadro devido as mudanças fisiológicas da gravidez, ressalta-se a importância da agilização diagnóstica e pronta instituição terapêutica, a fim de se evitar as principais complicações do quadro, como mortalidade materno-fetal e prematuridade.

Objetivo: Analisar o nível de conhecimento de Agentes Comunitários da Saúde (ACS’s) de uma Estratégia de Saúde da cidade de Belém - Pará sobre a depressão. Metodologia: Estudo transversal, descritivo e intervencionista, aprovado pelo Comitê de Ética em Pesquisa (CEP) que avaliou o conhecimento de ACS’s sobre depressão por meio de um questionário sóciodemográfico e um para avaliar o nível de conhecimentos sobre a patologia. Resultados: Participaram 11 ACS’s sendo 63,63% do sexo feminino, 54,55% com idade entre 30-39 anos, 54,55% possuíam ensino superior incompleto, 73% possuíam formação como ACS’s, 64% não conhecem nenhum método de prevenção da depressão (p

Objetivo: Descrever o perfil de hipertensos da área de abrangência de uma unidade de saúde em uma cidade da Amazônia – Brasil. Métodos: Pesquisa transversal, descritiva, observacional, epidemiológica, de análise dos prontuários de pacientes com Hipertensão Arterial Sistêmica cadastrados em uma área da cidade de Belém – Pará. Este projeto foi aprovado pelo Comitê de Ética em Pesquisa (CEP) sob parecer número 82845918.0.0000.5701. Resultados: Os resultados encontrados foram 120 hipertensos, sendo 63,17% do sexo feminino e o restante do sexo masculino. As mulheres tinham maior média de idade (65,01 anos comparado com 62,72 anos), contudo os homens possuíam maior média de peso (78,91 kg contra 64,09 kg) e altura (1,61m contra 1,49m). A maioria das mulheres (39,21%) e dos homens (48,28%) estavam na classificação Sobrepeso. Conclusão: O perfil de hipertensos na área de pesquisa é semelhante aos encontrados em outras áreas do país sendo necessário utilizar as informações do presente artigo para educação em saúde mais direcionada e eficiente sobre o assunto.

Interleukin (IL)-17D is a cytokine in the IL-17 family that is conserved in vertebrates and invertebrates. In contrast to IL-17A, which is expressed in T cells, IL-17D is expressed broadly in non-immune cells. IL-17D can promote immune responses to cancer and viruses in part by inducing chemokines that recruit natural killer cells and neutrophils. Although bacterial infection can induce IL-17D in other species, the role of mammalian IL-17D in anti-bacterial immunity has not been determined. In order to ascertain whether IL-17D has a role in mediating immunity against bacterial infections, we studied intraperitoneal infection by Group A Streptococcus (GAS) S. pyogenes in wild-type (WT) and IL-17D-deficient mice. We found that there was more weight loss and decreased survival in mice deficient in IL-17D compared to WT animals after GAS infection. In addition, IL-17D deficient animals had increased bacterial burden in the kidney and peritoneal cavity after GAS infection compared to WT animals. In WT animals, IL-17D transcript could be induced by GAS infection, correlating with increased levels of the chemokine CCL2 and neutrophil recruitment. Notably, GAS-mediated induction of IL-17D seemed to require live bacteria, indicating that pattern recognition did not mediate induction of IL-17D. Altogether, our results demonstrate a role for IL-17D in sensing replicating bacteria and inducing immune responses important in clearing bacteria in distant organs.

Colorectal cancer is a leading cause of cancer related deaths in the U.S., with African-Americans having higher incidence and mortality rates than Caucasian-Americans. Recent studies have demonstrated that anti-tumor cytotoxic T lymphocytes provide protection to patients with colon cancer while patients deficient in these responses have significantly worse prognosis. To determine if differences in cytotoxic immunity might play a role in racial disparities in colorectal cancer 258 microsatellite-stable colon tumors were examined for infiltrating immune biomarkers via immunohistochemistry. Descriptive summary statistics were calculated using two-sample Wilcoxon rank sum tests, while linear regression models with log-transformed data were used to assess differences in race and Pearson and Spearman correlations were used to correlate different biomarkers. The association between different biomarkers was also assessed using linear regression after adjusting for covariates. No significant differences were observed in CD8+ (p = 0.83), CD57+ (p = 0.55), and IL-17-expressing (p = 0.63) cell numbers within the tumor samples tested. When infiltration of granzyme B+ cells was analyzed, however, a significant difference was observed, with African Americans having lower infiltration of cells expressing this cytotoxic marker than Caucasians (p

Cells undergoing xenobiotic or oxidative stress activate the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2), which initiates an intrinsic "stress surveillance" pathway. We recently found that the cytokine IL-17D effects a form of extrinsic stress surveillance by inducing antitumor immunity, but how IL-17D is regulated remains unknown. Here, we show that Nrf2 induced IL-17D in cancer cell lines. Moreover, both Nrf2 and IL-17D were induced in primary tumors as well as during viral infection invivo. Expression of IL-17D in tumors and virally infected cells is essential for optimal protection of the host as il17d(-/-) mice experienced a higher incidence of tumors and exacerbated viral infections compared to wild-type (WT) animals. Moreover, activating Nrf2 to induce IL-17D in established tumors led to natural killer cell-dependent tumor regression. These data demonstrate that Nrf2 can initiate both intrinsic and extrinsic stress surveillance pathways and highlight the use of Nrf2 agonists as immune therapies for cancer and infection.

The oxidative stress-sensing transcription factor Nrf2 has been studied by cancer researchers as a double-edged sword that can either promote or inhibit cancer. Previous findings have shown that Nrf2 can act as a tumor suppressor by detoxifying carcinogens. Paradoxically, when cancer cells express Nrf2, they are protected from oxidative stress and certain chemotherapies, thus explaining why some cancer cells constitutively activate Nrf2 as a tumor promoter. We recently found that the cytokine Interleukin (IL)-17D mediates the recruitment of natural killer (NK) cells to tumor sites, thereby leading to tumor rejection. Here, we show that Nrf2 induced IL-17D in primary tumors and tumor cell lines. Moreover, the known Nrf2-activator tBHQ induced Nrf2 and IL-17D simultaneously, without creating harmful oxidative stress. Applying a tBHQ-containing skin cream to established tumors led to NK cell-mediated tumor regression, and this depended on IL-17D and Nrf2. We propose that the use of tBHQ or other Nrf2 activators can intiate a tumor surveillance pathway involving IL-17D and NK cells, thus mediating cancer regression and bearing potential for cancer immune therapy.

Antitumor immunity suppresses tumorigenesis, but we do not understand how transformed cells initiate those immune responses that are essential for effective tumor immunosurveillance. Using the 3-MCA fibrosarcoma model, we identified IL-17D as a tumor-expressed cytokine that recruits natural killer cells, leading to the polarization of M1 macrophages and tumor rejection.

The cancer stem cell (CSC) hypothesis stipulates that tumors follow a hierarchical organization where a subpopulation of cells endowed with stem cell characteristics initiates and maintains the malignant progression. Using the murine MCA sarcoma model system, a widely recognized model for studying cancer immunosurveillance and rejection mechanisms, we sought to explore how hierarchical tumor progression occurs during cancer immunosurveillance. The first step was to define CSC in the MCA sarcoma model. We identified an interesting heterogeneity of the tumor population based on Sca1 and CD90 expression. Purification of the Sca1+ and Sca1+/CD90+ in various cell lines and subsequent in vitro culture demonstrated that the Sca1+/CD90-population is able to regenerate the initial tumor heterogeneity. Transplantation of those two populations in RAGxγc-/- hosts demonstrated either a more rapid onset of sarcoma in mice injected with Sca1+ cells. Interestingly, phenotypic analysis of escaping tumors revealed an increase in Sca1+ cells. Finally, in vitro treatment with IFNg led to a substantial increase in Sca1 expression that correlated with an increase in cells' stemness properties as suggested by the elevated sphere forming capacity of IFNg treated cells. This data suggest that cancer stemness may be modulated by anti-cancer immune responses and may represent an additional mechanism of tumor immune escape.