The E-series prostaglandins (PGEs) are complex lipid regulators of B lymphocyte function. They inhibit the growth of certain B lymphoma lines. We report that heterogeneity with respect to PGE-induced growth inhibition correlates with the maturation state of the B cell lines. Specifically, the pre-B cell line 70 Z 3 and the immature lymphoma CH31 are extremely sensitive to PGE₂. To a lesser degree, other immature lymphomas (CH33, ECH408.1 and WEHI-231) are sensitive to PGE₂. More mature lymphomas (BAL-17, CH12 and CH27) and fully differentiated myelomas (J558 and MOPC-315) are insensitive to PGE₂. It is unknown what subtype of PGE receptors(s) (EPs) are expressed by B lymphocytes. It is also unknown if modulation of EP receptor expression could account for the differences in the sensitivity of these B cell lines to PGE₂. To investigate these issues, reverse transcriptase polymerase chain reaction, Northern blot and DNA sequencing analyses were employed to obtain a definitive EP receptor subtype profile for these B cell lines, and for normal splenic B lymphocytes. Both normal and transformed B lymphocytes express mRNA encoding EP₁, EP_3β and EP₄ subtypes of PGE receptors. The B lineage cells do not express EP_3α nor EP_3γ mRNA. The B cell lines are clonal, indicating that EP₁, EP_3β and EP₄ mRNA are coexpressed. Surprisingly, quantitative differences in basal EP₁, EP_3β and EP₄ expression were not observed between B cell lines despite their differing susceptibilities to PGE-induced growth inhibition. Conversely, the polyclonal activator LPS selectively upregulates EP₄ mRNA expression in the mature B cell line CH12, but not in the LPS-sensitive pre-B cell line, 70 Z 3 . The activator LPS does not affect EP₁ nor EP_3β mRNA expression. Treatment with dbcAMP, an analog of cAMP, mimics PGE-induced growth inhibition indicating that G_s-coupled EP₂ and/or EP₄ receptors mediate this inhibitory signal. Indeed, EP₂ agonists mimic PGE₂-induced growth inhibition unlike IP, EP₁ and EP₃-selective agonists. These data indicate that EP₂ receptors are sufficient for mediating PGE-induced growth inhibition of susceptible B lineage cells.