ABSTRACT
Syndecan-1 is a heparan sulfate proteoglycan (HSPG) commonly upregulated in AIDS-related B lymphoid malignancies. Tat is the main HIV-1 transactivating factor that has a major role in the pathogenesis of AIDS-related lymphomas (ARL) by engaging heparan sulfate proteoglycans (HSPGs), chemokine receptors and integrins at the lymphoid cell (LC) surface. Here B-lymphoid Namalwa cell clones that do not express or overexpress syndecan-1 (EV-Ncs and SYN-Ncs, respectively) were compared for their responsiveness with Tat: in the absence of syndecan-1, Tat induces a limited EV-Nc migration via C-X-C motif chemokine receptor 4 (CXCR4), G-proteins and Rac. Syndecan-1 overexpression increases SYN-Nc responsiveness to Tat and makes this response independent from CXCR4 and G-protein and dependent instead on pp60src phosphorylation. Tat-induced SYN-Nc migration and pp60src phosphorylation require the engagement of αvß3 integrin and consequent pp125FAK phosphorylation. This complex set of Tat-driven activations is orchestrated by the direct interaction of syndecan-1 with pp60src and its simultaneous coupling with αvß3. The Tat/syndecan-1/αvß3 interplay is retained in vivo and is shared also by other syndecan-1+ B-LCs, including BJAB cells, whose responsiveness to Tat is inhibited by syndecan-1 knockdown. In conclusion, overexpression of syndecan-1 confers to B-LCs an increased capacity to migrate in response to Tat, owing to a switch from a CXCR4/G-protein/Rac to a syndecan-1/αvß3/pp60src/pp125FAK signal transduction pathway that depends on the formation of a complex in which syndecan-1 interacts with Tat via its HS-chains, with αvß3 via its core protein ectodomain and with pp60src via its intracellular tail. These findings have implications in ARL progression and may help in identifying new therapeutical targets for the treatment of AIDS-associated neoplasia.
Subject(s)
Focal Adhesion Kinase 1/genetics , Integrin alphaVbeta3/genetics , Lymphocytes/metabolism , Neoplasms/genetics , Syndecan-1/genetics , Cell Adhesion/genetics , Gene Expression Regulation, Neoplastic , HIV-1/genetics , Humans , Lymphocytes/pathology , Multiprotein Complexes/genetics , Neoplasms/pathology , Phosphorylation , Proto-Oncogene Proteins pp60(c-src)/genetics , Receptors, CXCR4/genetics , Signal Transduction/genetics , tat Gene Products, Human Immunodeficiency Virus/administration & dosage , tat Gene Products, Human Immunodeficiency Virus/metabolismABSTRACT
A reduction in calorie intake [caloric restriction (CR)] appears to consistently decrease the biological rate of aging in a variety of organisms as well as protect against age-associated diseases including chronic inflammatory disorders such as cardiovascular disease and diabetes. Although the mechanisms behind this observation are not fully understood, identification of the main metabolic pathways affected by CR has generated interest in finding molecular targets that could be modulated by CR mimetics. This review describes the general concepts of CR and CR mimetics as well as discusses evidence related to their effects on inflammation and chronic inflammatory disorders. Additionally, emerging evidence related to the effects of CR on periodontal disease in non-human primates is presented. While the implementation of this type of dietary intervention appears to be challenging in our modern society where obesity is a major public health problem, CR mimetics could offer a promising alternative to control and perhaps prevent several chronic inflammatory disorders including periodontal disease.
Subject(s)
Caloric Restriction , Inflammation Mediators/antagonists & inhibitors , Inflammation/diet therapy , Adaptive Immunity , Animals , Biomimetics , Cardiovascular Diseases/diet therapy , Chronic Disease , Diabetes Mellitus/diet therapy , Humans , Immunity, Innate , Insulin-Like Growth Factor I/antagonists & inhibitors , Metformin/pharmacology , Periodontitis/diet therapy , Resveratrol , Signal Transduction/drug effects , Sirolimus/pharmacology , Sirtuins/drug effects , Stilbenes/pharmacology , TOR Serine-Threonine Kinases/antagonists & inhibitorsABSTRACT
Arousal is an important survival mechanism when infants are confronted with hypoxia during sleep. Many sudden infant death syndrome (SIDS) infants are exposed to repeated episodes of hypoxia before death and have impaired arousal mechanisms. We hypothesized that repeated exposures to hypoxia would cause a progressive blunting of arousal, and that a reversal of this process would occur if the hypoxia was terminated at the time of arousal. P5 (postnatal age of 5 days), P15, and P25 rat pups were exposed to either eight trials of hypoxia (3 min 5% O(2) alternating with room air) (group A), or three hypoxia trials as in group A, followed by five trials in which hypoxia was terminated at arousal (group B). In both groups A and B, latency increased over the first four trials of hypoxia, but reversed in group B animals during trials 5-8. Progressive arousal blunting was more pronounced in the older pups. The effects of intermittent hypoxia on heart rate also depended on age. In the older pups, heart rate increased with each hypoxia exposure. In the P5 pups, however, heart rate decreased during hypoxia and did not return to baseline between exposures, resulting in a progressive fall of baseline values over successive hypoxia exposures. In the group B animals, heart rate changes during trials 1-4 also reversed during trials 5-8. We conclude that exposure to repeated episodes of hypoxia can cause progressive blunting of arousal, which is reversible by altering the exposure times to hypoxia and the period of recovery between hypoxia exposures.
