The concept of mast cell heterogeneity has been studied extensively. Recently developed techniques to enzymatically disperse skin mast cells from human skin have shown that skin mast cells are somehow different from those of other organs such as lung and intestine. In this report, we have isolated and partially purified human skin mast cells from human neonatal foreskins by collagenase and hyaluronidase digestion. These mast cells are morphologically intact by histological, immunohistochemical and electron microscopic criteria. These human skin mast cells secrete histamine significantly (max. net histamine release, 20-30%) in a dose-related, temperature- and time-dependent fashion following stimulation with purified human C5a and C3a (over the ranges of 5 x 10(-8) M to 10(-7) M and 3 x 10(-7) M to 6 x 10(-6) M, respectively). On the other hand, interactions between human skin mast cells and other leukocytes have long been suspected of playing a very important role in cutaneous inflammation. Recently, a human neutrophil-derived histamine-releasing activity termed HRA-N was partially purified. HRA-N has been shown to cause human and rat basophil leukemia cells to degranulate. This study was also undertaken to assess the ability of HRA-N to directly induce histamine release from isolated human skin mast cells. HRA-N causes dose- and time-dependent histamine release as do human anaphylatoxins. These results suggest that HRA-N may lead to a better comprehension of allergic and inflammatory reactions and their modulation in the skin.