An interleukin 1 receptor antagonist blocks the IL-1-induced IL-6 paracrine production through a prostaglandin E2-related mechanism in multiple myeloma

Lu, Z. Y.; Bataille, R.; Poubelle, P.; Rapp, M. J.; Harousseau, J. L.; Klein, B.

Stem cells

1995-08 / vol 13 Suppl 2 / pages 28-34


By analogy with the model of pristane-induced mouse plasmacytomas, we have wondered about the putative role of prostaglandin E2 (PGE2) in the human multiple myeloma (MM) cytokine network, involving interleukin 6 (IL-6) and interleukin 1 (IL-1) as essential myeloma cell growth factors and inducing cofactors respectively. We show that PGE2 is produced in short-term cultures of bone marrow cells of patients with MM, concomitantly with both IL-6 and IL-1. Indomethacin, a potent inhibitor of cyclo-oxygenase and of PGE2 synthesis, significantly inhibits IL-6 production (but not IL-1 production) by 35% to 90% depending on the different MM patients studied and concurrently to that of PGE2. Exogenous PGE2 reverses this inhibition or even stimulates IL-6 production. An IL-1 receptor antagonist (IL-1RA) also significantly inhibits PGE2, IL-6 production and myeloma cell growth. The inhibition of IL-6 production is reversed by adding exogenous PGE2. These results show that induction of IL-6 by IL-1 is related to PGE2 in the bone marrow of patients with MM. Inhibition of PGE2 synthesis (as obtained with indomethacin and the IL-1RA) might be helpful to inhibit myeloma cell proliferation by reducing IL-1-induced endogenous IL-6 production not only in vitro (as demonstrated here) but also in vivo.

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Humans; Animals; Mice; Up-Regulation; Cell Division/drug effects; Dinoprostone/*biosynthesis; Indomethacin/pharmacology; Interleukin 1 Receptor Antagonist Protein; Interleukin-1/biosynthesis/*pharmacology; Interleukin-6/*biosynthesis; Multiple Myeloma/*immunology/*metabolism/pathology; Receptors, Interleukin-1/antagonists & inhibitors; Sialoglycoproteins/*pharmacology

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