PubMed · 2803306
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H A Papazian, L W Mason. 1989-10-16. Osmosis and microgravity.. https://doi.org/10.1016/0006-291x(89)91725-7
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IL-12 is a pivotal cytokine that links the innate and adaptive immune responses. TNF-alpha also plays a key role in orchestrating inflammation and immunity. The reciprocal influence of these two inflammatory mediators on each other may have significant impact on the cytokine balance that shapes the type and extent of immune responses. To investigate the relationship between TNF-alpha and IL-12 production, we analyzed the effects of exposure of human monocyte-derived macrophages to TNF-alpha on LPS- or Staphylococcus aureus-induced IL-12 production in the presence or absence of IFN-gamma. TNF-alpha is a potent inhibitor of IL-12 p40 and p70 secretion from human macrophages induced by LPS or S. aureus. IL-10 is not responsible for the TNF-alpha-mediated inhibition of IL-12. TNF-alpha selectively inhibits IL-12 p40 steady-state mRNA, but not those of IL-12 p35, IL-1alpha, IL-1beta, or IL-6. Nuclear run-on analysis identified this specific inhibitory effect at the transcriptional level for IL-12 p40 without down-regulation of the IL-12 p35 gene. The major transcriptional factors identified to be involved in the regulation of IL-12 p40 gene expression by LPS and IFN-gamma, i.e., c-Rel, NF-kappaB p50 and p65, IFN regulatory factor-1, and ets-2, were not affected by TNF-alpha when examined by nuclear translocation and DNA binding. These data demonstrate a selective negative regulation on IL-12 by TNF-alpha, identifying a direct negative feedback mechanism for inflammation-induced suppression of IL-12 gene expression.
The Leu-enkephalin analogue (Tyr-D-Ala-Gly-Phe-Leu-NH(2)) was synthesized together with three esters prodrugs hereof. The prodrugs synthesized were the O-acetyl, O-propionyl and O-pivaloyl99%) and in good yields (60-75%). The chemical and enzymatic stability of the prodrugs has been investigated in detail. The prodrugs studied are quite chemically stable and the degradation of the prodrugs follows the pattern previously shown for similar esters (U-shaped pH-profile; maximal stability at pH 4-5). The prodrugs are degraded quantitatively in plasma to the parent peptide with half-lives in the range 2.9 min-2.6 h. Type B esterases were shown to be involved in the degradation as the half-lives increased in the presence of paraoxon. No significant stabilization was seen in 10% porcine gut homogenate. Half-lives in the same order were seen for the analogue and the prodrugs in pure Leucine aminopeptidase solution. The analogue was stable in Carboxypeptidase A solution whereas a faster degradation of the prodrugs was seen in this media. Furthermore the transport properties of the compounds has been studied. A P(app) value of 0.284x10(-6) cm/s for the analogue was obtained for the transport across Caco-2 cell monolayers in the BL-AP direction. The P(app) values were increased by a factor of 2, 7 and 18 for the acetyl-, propionyl- and pivaloylprodrug. The increase could be explained by higher lipofilicities of the prodrugs compared to the analogue.
The influence of the nonchannel conformation of the transmembrane protein gramicidin A on the permeability coefficients of neutral and ionized alpha-X-p-methyl-hippuric acid analogues (XMHA) (X = H, OCH(3), CN, OH, COOH, and CONH(2)) across egg-lecithin membranes has been investigated in vesicle efflux experiments. Although 10 mol% gramicidin A increases lipid chain ordering, it enhances the transport of neutral XMHA analogues up to 8-fold, with more hydrophilic permeants exhibiting the greatest increase. Substituent contributions to the free energies of transfer of both neutral and anionic XMHA analogues from water into the bilayer barrier domain were calculated. Linear free-energy relationships were established between these values and those for solute partitioning from water into decadiene, chlorobutane, butyl ether, and octanol to assess barrier hydrophobicity. The barrier domain is similar for both neutral and ionized permeants and substantially more hydrophobic than octanol, thus establishing its location as being beyond the hydrated headgroup region and eliminating transient water pores as the transport pathway for these permeants, as the hydrated interface or water pores would be expected to be more hydrophilic than octanol. The addition of 10 mol% gramicidin A alters the barrier domain from a decadiene-like solvent to one possessing a greater hydrogen-bond accepting capacity. The permeability coefficients for ionized XMHAs increase with Na(+) or K(+) concentration, exhibiting saturability at high ion concentrations. This behavior can be quantitatively rationalized by Gouy-Chapman theory, though ion-pairing cannot be conclusively ruled out. The finding that transmembrane proteins alter barrier selectivity, favoring polar permeant transport, constitutes an important step toward understanding permeability in biomembranes.