Rtp801, a stress – related protein triggered by adverse environmental conditions, inhibits mTOR and enhances oxidative stress – dependent cell death. We postulated that Rtp801 acts as potential amplifying switch in the development of cigarette smoke – induced lung injury, leading to emphysema. Rtp801 was overexpressed in human emphysematous lungs and in lungs of mice exposed to cigarette smoke. The upregulation of Rtp801 expression by cigarette smoke in the lung relied on oxidative stress – dependent activation of the CCAAT response element. Rtp801 was necessary and sufficient for NF – κ B activation in cultured cells and, when forcefully expressed in mouse lungs, it promoted NF – kB activation, alveolar inflammation, oxidative stress, and apoptosis of alveolar septal cells. On the other hand, Rtp801 − / − mice were markedly protected against acute cigarette smoke – induced lung injury, partly via increased mTOR signaling, and, when exposed chronically, against emphysema. Our data support the notion that Rtp801 may represent an important molecular sensor and mediator of lung injury to cigarette smoke.
Airway responsiveness (AR) is determined by complex mechanisms reflecting lung responses to airborne stimuli. Murine studies have identified a number of potential factors modulating AR and thus have contributed to the current understanding of these mechanisms. In allergic inflammation, immune cells, in particular αβ T cells, have emerged as important contributors to increased AR. We have found that in contrast to αβ T cells, γδ T cells can have a negative regulatory effect on AR. Here, we review the current studies on γδ T cells in allergic inflammation and discuss their role in modulating AR. We propose that γδ T cells exhibit different immune properties depending on the type of stimulus and inflammation. These differential immune properties appear to be associated with specific γδ T cell subsets, which control AR to airborne stimuli. In particular, our recent data indicate that the Vγ4+ T cell subset acts as an important negative regulator of AR and contributes to maintaining normal lung function in mice.
Hydrostatic pressure (P) combined with membrane protein crosslinking (CL) by adenosine dialdehyde (AdA) can render tumor cells immunogenic. We have recently shown that PCL treatment of murine tumor cells augmented the presentation of MHC-restricted tumor-associated antigens and enhanced cell-mediated immunity. In cancer patients inoculated with autologous PCL-modified tumor cells, a significant delayed-type hypersensitivity response was elicited. Since the balance between cell-mediated immunity and humoral immunity is reciprocally controlled by immunoregulatory cytokines, we have examined the proliferative response and cytokine secretion pattern in cultures of human peripheral blood mononuclear cells (PBMC) stimulated by autologous PCL-modified and unmodified tumor cells. These tumor cells were obtained from freshly resected tumor tissue of 16 patients with colon (8), lung (4) and renal (4) carcinomas. The results demonstrated that PCL-modified tumor cells promoted an increase in PBMC proliferation in 5 out of 8 (63%), 1 out of 4 (25%) and 4 out of 4 (100%) colon, lung and renal cell carcinomas. Fourteen of the above cultures were also analyzed for the secretion of interleukin-10 and interferon-gamma. Overall, a substantial decrease in IL-10 secretion was detected in 9 out of 14 (64%) cultures while a reciprocal increase in interferon-gamma secretion was noted in 8 out of 14 (57%) cultures. Our results confirmed that PCL-modified human tumor cells of different etiologies can modulate the pattern of cytokines released from stimulated autologous lymphocytes. Such a procedure could prove valuable in the production of autologous tumor vaccines.
In the present study we show that a brief exposure of human PBMC to hydrostatic pressure (HyP) increased their proliferative response to PHA and anti-CD3 antibody, assessed by DNA synthesis. The effect of HyP was most prominent at 400 atmospheres of HyP followed by 600 and 200 atmospheres. At any pressure level, the highest effect of HyP was noted when employing PHA and anti-CD3 antibody at 10(-2) dilution. When PBMC were exposed to 400 atmospheres HyP, maximal effect was achieved at 20 minutes of exposure. The highest effect of HyP on DNA synthesis was noted at 48 and 72 hours of incubation with PHA, when exposing cells to pressure for 20 minutes at 400 atmospheres. Exposure of PBMC under similar conditions for 40 minutes, caused an increase in DNA synthesis only at 48 hours incubation with PHA. These results demonstrate that exposure of human PBMC to HyP increases their proliferative response to different polyclonal activators. The possible mechanisms involved in this phenomenon are discussed.
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