Prostanoid receptors mediating inhibition of anti‐IgE induced histamine release from rat peritoneal mast cells have been characterized pharmacologically. PGD₂ and the specific DP receptor agonists BW 245C and ZK 118182 were the most potent inhibitors with half‐maximal concentrations of 0.26, 0.06 and 0.02 μM respectively. The maximum inhibition attainable was 60–65% with 10⁻⁵ M BW 245C and ZK 118182. Among several EP receptor agonists investigated, only PGE₂ and the EP₂/EP₃ receptor agonist misoprostol induced significant inhibition (46.8±4.7% at 10⁻⁴ M and 18.7±6.8% at 10⁻⁵ M respectively). The IP receptor agonists cicaprost and iloprost were both less potent than the DP agonists in inhibiting histamine release (45.2±3.3% and 35.1±2.5% inhibition respectively at 10⁻⁵ M), whereas PGF_2α and the TP receptor agonist U‐46619 were only marginally effective. The EP₄/TP receptor antagonist AH 23848 failed to affect the inhibitory actions of PGD₂ or PGE₂ even at 10⁻⁵ M, whereas the DP/EP₁/EP₂ receptor antagonist AH 6809 slightly enhanced the effect of PGD₂ at 10⁻⁶ M. At concentrations of 3×10⁻⁶ to 10⁻⁵ M, the putative DP receptor antagonist ZK 138357 dose‐dependently suppressed the inhibitory activities of the DP agonists, PGE₂ and cicaprost. The antagonism of ZK 138357 against the DP receptor agonists appeared to be competitive with pA₂ values of around six. In conclusion, these data support our earlier proposal that an inhibitory DP receptor is the predominant prostanoid receptor in rat peritoneal mast cell. The properties of this receptor in relation to putative DP receptor subtypes reported in the literature are discussed. British Journal of Pharmacology (2000) 129, 589–597; doi:10.1038/sj.bjp.0703072

Agonists of CCR1 contribute to hypersensitivity reactions and atherosclerotic lesions, possibly via the regulation of the transcription factor STAT3. CCR1 was demonstrated to use pertussis toxin-insensitive Gα_14/16 to stimulate phospholipase Cβ and NF-κB, whereas both Gα₁₄ and Gα₁₆ are also capable of activating STAT3. The coexpression of CCR1 and Gα_14/16 in human THP-1 macrophage-like cells suggests that CCR1 may use Gα_14/16 to induce STAT3 activation. In this study, we demonstrated that a CCR1 agonist, leukotactin-1 (CCL15), could indeed stimulate STAT3 Tyr⁷⁰⁵ and Ser⁷²⁷ phosphorylation via pertussis toxin-insensitive G proteins in PMA-differentiated THP-1 cells, human erythroleukemia cells, and HEK293 cells overexpressing CCR1 and Gα_14/16. The STAT3 Tyr⁷⁰⁵ and Ser⁷²⁷ phosphorylations were independent of each other and temporally distinct. Subcellular fractionation and confocal microscopy illustrated that Tyr⁷⁰⁵-phosphorylated STAT3 translocated to the nucleus, whereas Ser⁷²⁷-phosphorylated STAT3 was retained in the cytosol after CCR1/Gα₁₄ activation. CCL15 was capable of inducing IL-6 and IL-8 (CXCL8) production in both THP-1 macrophage-like cells and HEK293 cells overexpressing CCR1 and Gα_14/16. Neutralizing Ab to IL-6 inhibited CCL15-mediated STAT3 Tyr⁷⁰⁵ phosphorylation, whereas inhibition of STAT3 activity abolished CCL15-activated CXCL8 release. The ability of CCR1 to signal through Gα_14/16 provides a linkage for CCL15 to regulate IL-6/STAT3–signaling cascades, leading to expression of CXCL8, a cytokine that is involved in inflammation and the rupture of atherosclerotic plaque.