AbstractCorticotropin releasing factor, adrenocorticotropic hormone (ACTH) and alpha‐melanocyte stimulating hormone either inhibit or enhance in a dose‐dependent fashion an interleukin‐4 (IL‐4) driven human IgE synthesisin vitro.Here, we show that culture conditions strongly influence the earlier observed dose‐ and donor‐dependent effects of adrenocorticotropic hormone. The effect of ACTH on IgE synthesis became only apparent late during culture periods, suggesting an indirect effect via the cellular microenvironment rather than by acting directly at the level of B‐cell isotype switching. Thus, we studied other proopiomelanocortin (POMC) derived peptides and neuropeptides known to influence the cellular microenvironment. Indeed, similar modulatory effects on IgE synthesis were also observed by the addition of other proopiomelanocortin‐derived peptides such as α‐, β‐, and γ‐endorphins as well as by the opioid binding pentapeptide Leu‐enkephalin. Furthermore the neuropeptide substance P accentuated an IL‐4 or an IL‐4 and anti‐CD40 antibody driven class switch to IgE. In contrast to ACTH, substance P interfered not only with IgE synthesis but also with the synthesis of the other immunoglobulin isotypes. Thus, systemically acting neuroendocrine peptides such as ACTH and locally acting neuropeptides such as the enkephalins and substance P can modulate the magnitude