TY - JOUR T1 - Modulation of tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, interleukin-8, and granulocyte/macrophage colony-stimulating factor expression in human monocytes by an endogenous anxiogenic benzodiazepine ligand, triakontatetraneuropeptide: evidence for a role of prostaglandins. JF - Molecular Pharmacology JO - Mol Pharmacol SP - 64 LP - 69 VL - 43 IS - 1 AU - V Taupin AU - J Gogusev AU - B Descamps-Latscha AU - F Zavala Y1 - 1993/01/01 UR - http://molpharm.aspetjournals.org/content/43/1/64.abstract N2 - Triakontatetraneuropeptide (TTN) is the major processing product of the endogenous anxiogenic peptide ligand of the benzodiazepine receptor, diazepam binding inhibitor. In the present study, we demonstrated by Northern blot analysis that the mRNA levels for tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 beta, granulocyte/macrophage colony-stimulating factor, IL-6, and IL-8 were significantly increased after 4 hr of incubation of human monocytes with lipopolysaccharide (LPS) and TTN (10(-11) M), compared with cells incubated with LPS alone. Exposure of monocytes for 20 hr to LPS and TTN (10(-11) M) also stimulated TNF-alpha, IL-1 beta and granulocyte/macrophage colony-stimulating factor release by 80%, 110%, and 98%, respectively, relative to the response elicited by LPS alone. Smaller stimulatory effects were observed using the prototypic pharmacological peripheral benzodiazepine Ro5-4864 (10(-11) M) (55%, 72%, and 62%, assessed by means of specific enzyme immunoassays). In contrast, TTN and Ro5-4864 did not modulate LPS-induced IL-6 and IL-8 production. Treatment with the cyclooxygenase inhibitor indomethacin increased IL-1 beta and TNF-alpha secretion but not that of IL-6 or IL-8. The observed stimulatory effects of TTN and indomethacin were not additive. Taken together, these findings suggest a common mechanism of action for TTN and indomethacin, involving PG formation. In this respect, TTN inhibited prostaglandin (PG) E2 production by 30%. The fact that the observed modulatory effects correlated with PG levels suggests the existence of a second-messenger pathway associated with the peripheral-type benzodiazepine receptor. These results indicate that human TTN differentially modulates the LPS-induced expression of proinflammatory cytokines, and they further support the concept that this endogenous psychoactive peptide could be involved in physiological control of the inflammatory response. ER -