PubMed · 1439132
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A C Allison, N E Byars. 1992. Syntex adjuvant formulation.. https://doi.org/10.1016/0923-2494(92)80063-q
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The synthetic immunomodulator murabutide has been found to suppress human immunodeficiency virus type-1 (HIV-1) replication, in macrophages, through a regulated expression of cellular factors needed at different steps in the virus replication cycle. To identify cellular genes implicated in the murabutide-induced virus inhibition, we have carried out a differential display analysis on HIV-1-infected macrophages that were treated, or not, with murabutide. Sequencing of the differentially regulated cDNA bands and verification of the reproducibility of the murabutide effects, by reverse transcription-polymerase chain reaction or by Northern blotting, revealed an up-regulated expression of 21 genes and a down-regulation of seven others. The murabutide-regulated genes encoded proteins implicated in DNA binding, regulation of transcription, oxidative stress, metal binding, and other physiological functions. Six of the genes corresponded to unassigned/expressed sequence tags with yet unknown function. Among the genes which were up-regulated by murabutide and with established effects on inhibiting virus transcription, was the octamer binding factor 1 (Oct-1). We demonstrate the ability of murabutide to induce enhanced Oct-1 protein expression and DNA-binding activity in macrophages. Furthermore, our findings suggest the potential implication of additional transcription factors and metal-binding proteins in mediating the inhibitory effect of murabutide on virus transcription.
Intravenous injection of lyophilized whole cells of various oral streptococcal strains into muramyldipeptide (MDP)-primed C3H/HeN mice induces rapid anaphylactoid shock. Here we examined the mechanism underlying this shock. In non-primed mice, Streptococcus intermedius K-213K (SiK213) and Streptococcus constellatus T21 (ScT21) produced little or no sign of shock. In MDP-primed mice, SiK213 caused lethal shock, while ScT21 only had a weak effect. SiK213 induced decreases in blood platelets and 5-hydroxytryptamine (5HT) preceding the shock, while the effects of ScT21 were weak. The SiK213-induced 5HT decrease and shock were reduced by a complement-C5 inhibitor. These results suggest that (i). streptococcal bacterial cells can induce rapid platelet responses, (ii). complement-dependent degradation of platelets may be involved in streptococcus-induced shock, (iii). the streptococcus-induced platelet degradation or degranulation may occur largely in the systemic circulation, and (iv). platelets may play a role not only in infectious diseases caused by gram-negative bacteria, but also in diseases caused by gram-positive bacteria.
Muropeptides contribute to the recognition of bacteria by modulating immune responses: the structural requirements for adjuvant activity were described in the seventies. During the last years, our knowledge of bacterial pattern recognition has increased dramatically and the importance of the absence of contaminations in both muropeptide preparations and other bacterial stimuli has become clear. We investigated a panel of 15 synthetic Limulus-negative muropeptides, four of them synthesized for the first time, as to their potency to synergize with lipopolysaccharide (LPS) in cytokine induction in human whole blood. No muropeptide was capable of stimulating cytokine release from human blood. However, as little as 20 nM of the muropeptides N-acetyl-muramyl-l-alanyl-d-isoglutamine (muramyl dipeptide, M(AdiQ)), N-acetyl-glucosamine-muramyl dipeptide GM(AdiQ), or C(18)M(AdiQ), which carries a non-natural additional fatty acid, sufficed to induce an up to 3 log-order shift in tumor necrosis factor alpha-release in response to 100 pg/ml LPS. The release of interleukin-1beta, interleukin-6, and interleukin-10 was also significantly enhanced although to a lesser extent. The synergistic effect was stereoselective with M(AdiQ) being the minimal active principle. Synergy was also observed on the transcriptional level by means of real-time PCR. Smaller molecules like N-acetylmuramic acid (M), aM, carrying a naturally occurring 1,6-anhydro-bound in M or M(A), containing only the amino acid l-alanine neither synergized with LPS nor influenced the synergy of other muropeptides with LPS. In conclusion, these data show that nanomolar quantities of muropeptides dramatically potentiate LPS-induced monocyte activation. This has implications for pyrogenicity testing and endotoxemia in patients.