Initial exposure of monocytes/macrophages to LPS induces hyporesponsiveness to a second challenge with LPS, a phenomenon termed LPS tolerance. Molecular mechanisms responsible for endotoxin tolerance are not well defined. We and others have shown that IL-1R–associated kinase (IRAK)-M and SHIP-1 proteins, negative regulators of TLR4 signaling, increase in tolerized cells. TGF-β1, an anti-inflammatory cytokine, is upregulated following LPS stimulation, mediating its effect through SMAD family proteins. Using a monocytic cell line, THP1, we show that LPS activates endogenous SMAD4, inducing its migration into the nucleus and increasing its expression. Secondary challenge with high dose LPS following initial low-dose LPS exposure does not increase IRAK-M or SHIP1 protein expression in small hairpin (sh)SMAD4 THP-1 cells compared with control shLUC THP1 cells. TNF-α concentrations in culture supernatants after second LPS challenge are higher in shSMAD4 THP-1 cells than shLUC THP1 cells, indicating failure to induce maximal tolerance in absence of SMAD4 signaling. Identical results are seen in primary murine macrophages and mouse embryonic fibroblasts, demonstrating the biological significance of our findings. TGF-β1 treatment does not increase IRAK-M or SHIP1 protein expression in shSMAD4 THP-1 cells, whereas it does so in shLUC THP1 cells, indicating that TGF-β1 regulates IRAK-M and SHIP1 expression through a SMAD4-dependent pathway. Knockdown of endogenous SHIP1 by shSHIP1 RNA decreases native and inducible IRAK-M protein expression and prevents development of endotoxin tolerance in THP1 cells. We conclude that in THP-1 cells and primary murine cells, SMAD4 signaling is required for maximal induction of endotoxin tolerance via modulation of SHIP1 and IRAK-M.
We have developed a portable near-infrared laser heterodyne radiometer (LHR) for quasi-simultaneous measurements of atmospheric carbon dioxide (CO2), methane (CH4), water vapor (H2O) and oxygen (O2) column absorption by using three distributed-feedback diode lasers as the local oscillators of the heterodyne detection. The developed system shows good performance in terms of its high spectral resolution of 0.066 cm−1 and a low solar power detection noise which was about 2 times the theoretical quantum limit. Its measurement precision of the column-averaged mole fraction for CO2 and CH4 is within 1.1%, based on the standard deviation from the mean value of the retrieved results for a clean sky. The column abundance information of the O2 is used to correct for the variations and uncertainties of atmosphere pressure, the solar altitude angle, and the prior profiles of pressure and temperature. Comparison measurements of daily column-averaged atmospheric mole fractions of CO2, CH4 and H2O, between our developed LHR and a greenhouse gas observing satellite, show a good agreement, which proves the reliability of our developed system.
Tunable diode laser absorption spectroscopy has been widely employed for gas sensing, where the gas concentration is often obtained from the absorption signal with a known or a fixed absorption path length. Nevertheless, there are also numerous applications in which the absorption path length is very challenging to retrieve, e.g., open path remote sensing and gas absorption in scattering media. In this work, a new approach, based on the wavelength modulation spectroscopy (WMS), has been developed to measure the gas absorption signal and the corresponding absorption path length simultaneously. The phase angle of the first harmonic signal (1f phase angle) in the WMS technique is utilized for retrieving the absorption path length as well as the gas absorption signal. This approach has been experimentally validated by measuring carbon dioxide (CO2) concentration in open path environment. The CO2 concentration is evaluated by measuring the reflectance signal from a distant object with hundreds of meters away from the system. The measurement accuracy of the absorption path length, evaluated from a 7-day continuous measurement, can reach up to 1%. The promising result has shown a great potential of utilizing the 1f phase angle for gas concentration measurements, e.g., open path remote sensing applications.
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