A ROLE FOR CALCITONIN-GENE-RELATED PEPTIDE (CGRP) IN THE REGULATION OF EARLY B-LYMPHOCYTE DIFFERENTIATION

In previous studies we identified high affinity adenylyl cyclase linke d receptors for calcitonin gene related peptide (CORP) on rat T and B cells, on lymphocyte cell lines including the mouse pre-B cell line 70 Z/3, and on cells in mouse bone marrow. The effect of CGRP on early B cell differentiation has been examined using the 70Z/3 cell line. CGRP inhibits the lipopolysaccharide (LPS) induction of surface immunoglob ulin (sig) protein expression in 70Z/3 cells, an effect that is associ ated with a decrease in the steady-state levels of Ig heavy (mu) and l ight (kappa) chain mRNA. In this report, experiments are described tha t provide further information on the mechanism by which CORP inhibits sig expression. The kinetics of CORP inhibition of LPS-induced sig exp ression was examined in 70Z/3 cells. An optimal window for the inhibit ory effect of CORP on sig induction occurs at least 24 h after the cel ls are treated with LPS. To determine whether the inhibitory effects o f CGRP on sig expression are mediated by an inhibition of NK kappa-B t ranslocation to the nucleus, electrophoretic mobility shift assays wer e performed using nuclear proteins from 70Z/3 cells. There was no diff erence in NF kappa-B binding activity in cells that had been treated w ith LPS or LPS + CORP, suggesting that the inhibitory effect of CORP i s not mediated by an inhibition of NF kappa-B activity. These studies provide further evidence that CORP plays an inhibitory role in early B cell differentiation. Finally, a model is proposed that describes an integrated role for CORP in the homeostatic regulation of early B cell differentiation.