RESUMEN
Cancer is the second leading cause of death globally and its incidence and mortality are rapidly increasing worldwide. The dynamic interaction of immune cells and tumor cells determines the clinical outcome of cancer. Immunotherapy comes to the forefront of cancer treatments, resulting in impressive and durable responses but only in a fraction of patients. Thus, understanding the characteristics and profiles of immune cells in the tumor microenvironment (TME) is a necessary step to move forward in the design of new immunomodulatory strategies that can boost the immune system to fight cancer. Histamine produces a complex and fine-tuned regulation of the phenotype and functions of the different immune cells, participating in multiple regulatory responses of the innate and adaptive immunity. Considering the important actions of histamine-producing immune cells in the TME, in this review we first address the most important immunomodulatory roles of histamine and histamine receptors in the context of cancer development and progression. In addition, this review highlights the current progress and foundational developments in the field of cancer immunotherapy in combination with histamine and pharmacological compounds targeting histamine receptors.
Asunto(s)
Histamina/metabolismo , Neoplasias/metabolismo , Receptores Histamínicos/metabolismo , Microambiente Tumoral/inmunología , Inmunidad Adaptativa/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Linfocitos B/inmunología , Linfocitos B/metabolismo , Basófilos/inmunología , Basófilos/metabolismo , Histamina/inmunología , Humanos , Inmunidad Innata/inmunología , Inmunoterapia , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Mastocitos/inmunología , Mastocitos/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Neutrófilos/inmunología , Neutrófilos/metabolismo , Receptores Histamínicos/inmunología , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
Inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, and leukotrienes, impact the immune system, usually as proinflammatory factors. Other mediators act as regulatory components to establish homeostasis after injury or prevent the inflammatory process. Histamine, a biogenic vasoactive amine, causes symptoms such as allergies and has a pleiotropic effect that is dependent on its interaction with its four histamine receptors. In this review, we discuss the dualistic effects of histamine: how histamine affects inflammation of the immune system through the activation of intracellular pathways that induce the production of inflammatory mediators and cytokines in different immune cells and how histamine exerts regulatory functions in innate and adaptive immune responses. We also evaluate the interactions between these effects.
Asunto(s)
Histamina/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inmunidad Adaptativa/inmunología , Animales , Citocinas/metabolismo , Humanos , Inmunidad Innata/inmunología , Receptores Histamínicos/inmunología , Receptores Histamínicos/metabolismoRESUMEN
The histamine receptors (HRs) are members of G-protein-coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H3 R and H4 R have been explored as targets for drug discovery, including in the search for dual-acting H3 R/H4 R ligands. The H4 R, the most recent histamine receptor, is a promising target for novel anti-inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1-[(2,3-dihydro-1-benzofuran-2-yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H3 R/H4 R ligands herein. The results showed the compounds presented affinity (Ki ) for H3 R/H4 R in micromolar range, and they are more selective to H3 R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl-substituted compound LINS01005 has shown the higher affinity of the set for H4 R, but no considerable selectivity toward this receptor over H3 R. LINS01005 showed interesting anti-inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX-2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti-inflammatory agents.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Piperazinas/química , Piperazinas/farmacología , Receptores Acoplados a Proteínas G/inmunología , Receptores Histamínicos H3/inmunología , Receptores Histamínicos/inmunología , Animales , Antiinflamatorios/síntesis química , Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Asma/inmunología , Benzofuranos/síntesis química , Benzofuranos/química , Benzofuranos/farmacología , Benzofuranos/uso terapéutico , Humanos , Piperazinas/síntesis química , Piperazinas/uso terapéutico , Ratas , Receptores Histamínicos H4RESUMEN
Histamine is a chemical transmitter found practically in whole organism and exerts its effects through the interaction with H1 to H4 histaminergic receptors. Specifically, H4 receptors are found mainly in immune cells and blood-forming tissues, thus are involved in inflammatory and immune processes, as well as some actions in central nervous system. Therefore, H4 receptor ligands can have applications in the treatment of chronic inflammatory and immune diseases and may be novel therapeutic option in these conditions. Several H4 receptor ligands have been described from early 2000's until nowadays, being imidazole, indolecarboxamide, 2-aminopyrimidine, quinazoline, and quinoxaline scaffolds the most explored and discussed in this review. Moreover, several studies of molecular modeling using homology models of H4 receptor and QSAR data of the ligands are summarized. The increasing and promising therapeutic applications are leading these compounds to clinical trials, which probably will be part of the next generation of blockbuster drugs.
Asunto(s)
Descubrimiento de Drogas , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Animales , Descubrimiento de Drogas/métodos , Humanos , Imidazoles/química , Imidazoles/farmacología , Indoles/química , Indoles/farmacología , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Ligandos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacología , Quinazolinas/química , Quinazolinas/farmacología , Quinoxalinas/química , Quinoxalinas/farmacología , Receptores Acoplados a Proteínas G/inmunología , Receptores Histamínicos/inmunología , Receptores Histamínicos H4 , Relación Estructura-ActividadRESUMEN
Viruses are associated with the development of periodontal disease, particularly during periods of suppressed cellular immunity. For this reason, we evaluated the hypothesis that viral components regulate the actions of histamine, an important mediator of immune responses. We assessed the effect of Poly (I:C) on histamine-mediated intracellular calcium mobilization in human gingival fibroblasts. Our results show that histamine induces an increase in intracellular calcium concentrations in a dose-dependent manner. This response was blocked when cells were incubated in the presence of Poly (I:C). In addition, phorbol esters, a diacylglycerol analog, mimics the inhibitory actions of Poly (I:C) in response to histamine. The effect of Poly (I:C) was reversed by Stuarosporine (1 µM), GÖ6983 (7 µM), Bisindolylmaleimide (1 µM) [a protein inhibitor (PKC)], and SB 203580 (3 µM) (a p38-MAPK inhibitor). These findings suggest that Poly (I:C) regulates histamine-induced calcium mobilization through activation of PKC and p38.
Asunto(s)
Fibroblastos/metabolismo , Encía/metabolismo , Histamina/farmacología , Poli I-C/farmacología , Receptores Histamínicos/metabolismo , Receptor Toll-Like 3/metabolismo , Calcio/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Fibroblastos/efectos de los fármacos , Fibroblastos/inmunología , Encía/citología , Encía/inmunología , Histamina/metabolismo , Humanos , Indoles/farmacología , Maleimidas/farmacología , Fosforilación , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Receptores Histamínicos/inmunología , Transducción de Señal , Acetato de Tetradecanoilforbol/farmacología , Receptor Toll-Like 3/inmunología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The role of mast cell mediators on cervical cancer cell migration was assessed using an in vitro assay of scratch wound healing onto monolayers of HPV18-positive cervical carcinoma cells (SW756). Migration of SW756 cells was accelerated by co-culture with the mast cell line LAD2. This effect was inhibited by the H1R antagonist pyrilamine and the cannabinoid agonists 2-arachidonylglycerol (2AG) and Win 55,212-2. Therefore, the specific effects of histamine and cannabinoids on SW756 migration and LAD2 activation were analyzed. Histamine added to the in vitro assay of scratch wound healing either increased or inhibited SW756 migration rate by acting either on H1R or H4R, respectively. Cannabinoids acted on CB1 receptors to inhibit SW756 migration. Supernatants from SW756 cells stimulated LAD2 cell degranulation, which in turn was inhibited by cannabinoids acting via CB2 receptors. RT-PCR showed that SW756 expressed mRNA for CB1, CB2, H1R, H2R, and H4R. On the other hand, LAD2 expressed mRNA for all four HRs and CB2. The results suggest that mast cells could be contributing to cervical cancer cell invasion and spreading by the release of histamine and cannabinoids. Therefore, therapeutic modulation of specific mast cell mediators may be beneficial for cervical cancer treatment.