Activation of bronchial epithelial cells (BEC) and disruption of an intact epithelial barrier in a lung transplant recipient can lead to acute or chronic rejection, events that are associated with release of soluble human leukocyte antigen (sHLA) class I. Although we know that HLA is released from mitogen-activated lymphocytes in a metalloproteinase (MPase)-dependent fashion, the mechanism of release from nonlymphoid tissue is not well understood. To this end, we stimulated primary BEC with increasing amounts of the T-helper cell-1 cytokines, interferon gamma (IFNgamma), and/or tumor necrosis factor alpha (TNFalpha) and measured the quantity and forms of HLA class I release. We found that IFNgamma, but not TNFalpha, was able to stimulate a time- and concentration-dependent release of HLA/beta(2)m and beta(2)m-free heavy chain (HC) from the BEC. A portion (50%) of the HLA/beta(2)m release and >90% of the beta(2)m-free HC release was mediated by a MPase. Western blot analysis supported the conclusion that a MPase-sensitive pathway produced 36 and 37 kDa cleaved forms, whereas the secreted 39 kDa form of beta(2)m-associated soluble HLA class I (sHLA/beta(2)m) was MPase-resistant. This adds to the growing understanding of the extracellular processing pathways of major histocompatibility complex class I that may be critical for both chronic rejection as well as immune regulation.