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Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Vasoactive Intestinal Peptide (VIP) Stimulate Interleukin-6 Production through the Third Subtype of PACAP/VIP Receptor in Rat Bone Marrow-Derived Stromal Cells

From Institute for Animal Experimentation (Y.C., X.X., T.Y., K.M.), and Second Department of Pathology (H.U.), University of Tokushima School of Medicine, Tokushima 770, and Institute for Experimental Animal Science (G.-J.S., Y.M., T.A.), Nagoya City University Medical School, Nagoya 467, Japan

Address all correspondence and requests for reprints to: Kozo Matsumoto, Institute for Animal Experimentation, University of Tokushima School of Medicine, Tokushima 770, Japan.

Regulation of Interleukin-6 (IL-6) production in bone marrow (BM)-derived stromal cells by neuropeptides, pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP), was examined. Both forms of PACAP, PACAP-27 and PACAP-38, as well as VIP significantly increased IL-6 production by rat BM-derived stromal cells at physiological concentrations ranging from 10^-10–10^-8 M. The three related peptides (PACAP-27, -38, and VIP) stimulated the production of both cAMP and inositol 1,4,5-trisphosphate (IP₃) in rat BM-derived stromal cells with similar 50% effective concentrations. The stimulatory potency of the three related peptides for the production of IL-6, cAMP, and IP₃ was almost consistent, suggesting that the dual signaling transduction pathways may be involved in PACAP/VIP-induced IL-6 production in rat BM-derived stromal cells. The messenger RNA (mRNA) for the third subtype of PACAP receptor (PVR3) was found to be abundantly expressed in both BM-derived stromal cells and the BM tissue, whereas little of the mRNA for type 1 (PVR1) nor type 2 (PVR2) was detected. Furthermore, the mRNAs for PACAP and VIP were detected in the BM tissue, suggesting that both PACAP/VIP and PVR3 are synthesized in vivo in the BM. The results shown in this paper suggest that PACAP/VIP and their receptor play an important role in the IL-6 production and perhaps in the hematopoiesis in the BM.

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