RESUMEN
In an ever-changing environment, an adaptive stress response is the pivotal regulatory mechanism to maintain allostasis. Physiologic responses to stressors enable to overcome potential threat. Glucocorticoid effects can be considered compensatory and adaptive, however prolonged or excessive glucocorticoid secretion can be also maladaptive and detrimental. Therefore, it must be tightly regulated. Apart from the essential hormonal feedback regulation, evidence accrues that cytokines, e.g., proinflammatory interleukin 1ß (IL-1ß), also play an important regulatory role in the stress axis. Here we focused on the potential role of CXC chemokines (CXCL8 and CXCL12) and their receptors (CXCR1, 2 and 4) in the regulation of the stress response in common carp. We studied changes in gene expression of CXC chemokines and CXCRs in the stress axis organs (hypothalamus-pituitary gland-head kidney) upon 11 h of restraint stress and we established how CXCR blocking affects the activation of the stress axis and the synthesis/conversion of cortisol. During restraint stress, gene expression of the majority of the proinflammatory CXCL8 and homeostatic CXCL12 chemokines and their receptors was upregulated in the stress axis organs. Inhibition of CXCR1-2 and CXCR4 differentially affected the expression of genes encoding stress-related molecules: hormones, binding proteins, receptors as well as expression of genes encoding IL-1ß and its receptor. Moreover, we observed that CXC chemokines, via interaction with their respective CXCRs, regulate gene expression of molecules involved in cortisol synthesis and conversion and consistently affect the level of cortisol released into the circulation during the stress response. We revealed that in fish, CXC chemokines and their receptors are important regulators of the stress response at multiple levels of the stress axis, with particularly pronounced effects on steroidogenesis and cortisol conversion in the head kidney.
Asunto(s)
Carpas , Hidrocortisona , Animales , Carpas/genética , Carpas/metabolismo , Glucocorticoides , Interleucina-8 , Receptores de Interleucina-8A/genéticaRESUMEN
Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphorus flame retardant that has been utilized in recent years as a primary replacement for polybrominated diphenyl ethers (PBDEs) in a wide variety of fire-sensitive applications. However, the impact of TDCPP on the immune system has not been fully determined. As the largest secondary immune organ in the body, the spleen is considered to be an important study endpoint for determining immune defects in the body. The aim of this study is to investigate the effect of TDCPP toxicity on the spleen and its possible molecular mechanisms. In this study, for 28 consecutive days, TDCPP was administered intragastrically (i.g), and we assessed the general condition of mice by evaluating their 24 h water and food intake. Pathological changes in spleen tissues were also evaluated at the end of the 28-day exposure. To measure the TDCPP-induced inflammatory response in the spleen and its consequences, the expression of the critical players in the NF-κB pathway and mitochondrial apoptosis were detected. Lastly, RNA-seq was performed to identify the crucial signaling pathways of TDCPP-induced splenic injury. The results showed that TDCPP intragastric exposure triggered an inflammatory response in the spleen, likely through activating the NF-κB/IFN-γ/TNF-α/IL-1ß pathway. TDCPP also led to mitochondrial-related apoptosis in the spleen. Further RNA-seq analysis suggested that the TDCPP-mediated immunosuppressive effect is associated with the inhibition of chemokines and the expression of their receptor genes in the cytokine-cytokine receptor interaction pathway, including four genes of the CC subfamily, four genes of the CXC subfamily, and one gene of the C subfamily. Taken together, the present study identifies the sub-chronic splenic toxicity of TDCPP and provides insights on the potential mechanisms of TDCPP-induced splenic injury and immune suppression.
RESUMEN
Chemokines are signaling proteins secreted by immune cells which regulate leukocyte trafficking. The aberrant expression of chemokines and their receptors by neoplastic cells influences the behaviour of many human cancers. This study evaluated gene-expression of the chemokines: CCL5, CXCL10, CXCL12 and the chemokine receptors: CXCR3, CXCR4, CXCR7, CCR4, CCR9 in 41 histologically-malignant, outcome-known, canine mammary tumours. These chemokines and chemokine receptors were selected as all were previously shown to influence the behaviour of human breast cancers. The expression of chemokines CCL5 and CXCL12 were significantly higher in tumours which subsequently metastasised than tumours that did not metastasise (p < 0.05). Increased expression of these chemokines was also correlated with shorter survival times of the dogs (CCL5: rs = -0.40, p = 0.02, CXCL12: rs = -0.40, p = 0.03) while CCL5 was independently prognostic of survival times (p = 0.026). A significantly higher proportion of tumours that subsequently metastasised expressed CXCR3 (p = 0.037), CXCR4 (p = 0.026), CXCR7 (p = 0.025) and CCR9 (p = 0.039) receptors while the survival times of the dogs with tumours that expressed CXCR4 (p = 0.045) and CCR9 (p = 0.039) receptors were significantly shorter than dogs with tumours that did not express these receptors. Chemokine and chemokine receptor gene-expression has not been previously correlated with disease outcome of canine mammary tumours. These findings indicate that altered expression of chemokines and their receptors influences the behaviour of canine mammary tumours suggesting a potential role of them as prognostic markers or therapeutic targets.
Asunto(s)
Quimiocinas/genética , Enfermedades de los Perros/inmunología , Neoplasias Mamarias Animales/inmunología , Metástasis de la Neoplasia/genética , Animales , Línea Celular Tumoral , Movimiento Celular , Quimiocinas/inmunología , Enfermedades de los Perros/genética , Perros , Femenino , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Metástasis de la Neoplasia/inmunología , Pronóstico , Transducción de SeñalRESUMEN
Recent studies indicate that chemoattractant cytokines (chemokines) and their receptors modulate intestinal B lymphocytes in different ways, including regulating their maturity and differentiation in the bone marrow and homing to intestinal target tissues. Here, we review several important chemokine/chemokine receptor axes that guide intestinal B cells, focusing on the homing and migration of IgA antibody-secreting cells (IgA-ASCs) to intestinal-associated lymphoid tissues. We describe the selective regulation of these chemokine axes in coordinating the IgA-ASC trafficking in intestinal diseases. Finally, we discuss the role of B cells as chemokine producers serving dual roles in regulating the mucosal immune microenvironment.