Relationship between dehydroepiandrosterone and calcitonin gene-related peptide in the mouse thymus

Abstract

Dehydroepiandrosterone (DHEA) and calcitonin gene-related peptide (CGRP) are naturally occurring substances that are reported to have both opposing and complementary effects on immune functions. In the current study, we sought to determine how they might work together to influence the mitogen-stimulated proliferation of thymocytes. In concanavalin A (ConA)-induced thymocyte proliferation assays, CGRP and DHEA each inhibited proliferation. When the CGRP antagonist CGRP-(8-37) was added to Con A-stimulated thymocytes, the proliferative response was significantly greater than the ConA response alone across a range of ConA doses. Moreover, CGRP-(8-37) blocked the inhibitory effect of DHEA. Individually, CGRP-(8-37), CGRP, DHEA, or their combination did not stimulate thymocyte proliferation in the absence of ConA. CGRP affects the proliferation of CD4+ T cells and thus may be a regional endogenous inhibitor of the proliferation of virgin mature T cells while they remain in the thymus. Furthermore, DHEA may act via endogenous CGRP on the thymus CD4+ T cell population.

Rat-2 fibroblasts express specific adrenomedullin receptors, but not calcitonin-gene-related-peptide receptors, which mediate increased intracellular cAMP and inhibit mitogen-activated protein kinase activity

“…However, mesangial cells express CGRP receptors [48] and, as adrenomedullin is capable of acting via CGRP receptors to increase cAMP [17], this cannot be discounted as a mechanism in mesangial cells. In support of this hypothesis, CGRP is able to inhibit thymocyte [49] and splenocyte [50] cell growth. Rat-2 cells, however, do not express CGRP receptors, and it can be concluded that, in these cells, adrenomedullin is acting via specific receptors to increase intracellular cAMP and inhibit MAPK activation.…”

Autonomic innervation of immune organs and neuroimmune modulation

“…, 1994; Kurz, von Gaudecker, Kranz, Krisch & Mentlein, 1995; Bulloch, McEwen, Nordberg, Diwa & Baird, 1998). Functional and pharmacological analyses have shown that CGRP mediates different immune responses of thymocytes via distinct receptor subtypes (Bulloch, McEwen, Diwa & Baird, 1995; Bulloch et al. , 1998).…”

“…SP binding sites were also found in rat thymocytes (Shigematsu, Saavedra & Kurihara, 1986; Elands, Resink & De Kloet, 1990). CGRP and SP probably represent fundamental physiological regulatory substances playing a critical role in differentiation, maturation and proliferation of thymocytes and are more likely to be implicated in promoting apoptosis in the thymus (Bulloch et al. , 1994, 1995, 1998; Kurz et al.…”

“…Moreover, steroids in interplay with the T‐cell receptor (TCR) trigger, may be involved in T cell differentiation‐related life/death decisions in the thymus (Vacchio, Paradopoulos & Ashwell, 1994). Functional studies indicate that CGRP is a potent inhibitor of concanavalin A (con‐A)‐stimulated proliferation of thymocytes (Bulloch et al. , 1994, 1995, 1998).…”

“…, 1994, 1995, 1998). CGRP affects the proliferation of CD4‐positive T cells suggesting that the neuropeptide may be an inhibitor of the proliferation of virgin mature T cells while they remain in the thymus (Bulloch et al. , 1995).…”