Evidence for paracrine signaling between macrophages and bovine adrenal chromaffin cell Ca²⁺ channels

The adrenal gland contains resident macrophages, some of which lie adjacent to the catecholamine producing chromaffin cells. Because macrophages release a variety of secretory products, it is possible that paracrine signaling between these two cell types exists. Of particular interest is the potential paracrine modulation of voltage-gated calcium channels (I(Ca)), which are the main calcium influx pathway triggering catecholamine release from chromaffin cells. We report that prostaglandin E₂ (PGE₂), one of the main signals produced by macrophages, inhibited I(Ca) in cultured bovine adrenal chromaffin cells. The inhibition is rapid, robust, and voltage dependent; the activation kinetics are slowed and inhibition is largely reversed by a large depolarizing prepulse, suggesting that the inhibition is mediated by a direct G-protein βγ subunit interaction with the calcium channels. About half of the response to PGE₂ was sensitive to pertussis toxin (PTX) incubation, suggesting both PTX-sensitive and -insensitive G proteins were involved. We show that activation of macrophages by endotoxin rapidly (within minutes) releases a signal that inhibits I(Ca) in chromaffin cells. The inhibition is voltage dependent and partially PTX sensitive. PGE₂ is not responsible for this inhibition as blocking cyclooxygenase with ibuprofen did not prevent the production of the inhibitory signal by the macrophages. Nor did blocking the lipoxy-genase pathway with nordihydroguaiaretic acid alter production of the inhibitory signal. Our results suggest that macrophages may modulate I(Ca) and catecholamine secretion by releasing PGE₂ and other chemical signal(s).