Human Keratinocytes Acquire Cellular Cytotoxicity under UV-B Irradiation

Abstract

Ultraviolet (UV) radiation from the sun is widely considered as a major cause of human skin photoaging and skin cancer. Granzyme B (GrB) and perforin (PFN) are two proteins contained in granules and implicated in one of the mechanisms by which cytotoxic lymphocytes and natural killer cells exert their cytotoxicity against virus-infected, alloreactive, or transformed cells. The distribution of GrB and PFN in the skin has received little attention. However, Berthou and co-workers (Berthou, C., Michel, L., Soulie, A., JeanLouis, F., Flageul, B., Dubertret, L., Sigaux, F., Zhang, Y., and Sasportes, M. (1997) J. Immunol. 159, 5293-5300) described that, whereas freshly isolated epidermal cells did not express GrB or PFN, keratinocyte growth to confluence was associated with GrB and PFN mRNA and protein synthesis. In this work, we have investigated the possible role of UV-B on GrB and PFN expression in keratinocytes. We found that UV-B induces GrB and PFN expression in these cells through redox-, epidermal growth factor receptor-, and mitogen-activated protein kinase-dependent signaling. Furthermore, under UV irradiation, keratinocytes acquire a significant cytotoxicity, which is GrB and PFN dependent, toward a variety of cellular targets including transformed T-lymphocytes, melanocytes, and keratinocytes. This phenomenon may have important functional consequences in the regulation of skin inflammatory response and in the emergence of cancer skin.

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

“…It is unclear whether, during killer cell degranulation, the immune synapse forms a perfectly tight gasket that completely prevents granzymes from leaking out into the extracellular space. Moreover, increasing evidence suggests that granzymes may be expressed without perforin and secreted by other types of white blood cells during inflammation, including mast cells, neutrophils, activated macrophages, as well as potentially some nonhematopoietic cells, such as UV-damaged keratinocytes (7,10,11,(176)(177)(178). GzmB is even expressed by developing germ cells in the testes and by syncytial trophoblasts in the placenta (14).…”

Control of granzymes by serpins

“…25 However, it is now apparent that gzmB is expressed by a great diversity of cell types, including cells of both the myeloid [26][27][28][29] and lymphoid lineages, [30][31][32][33] as well as cells outside the immune system. 22,34,35 Thus, the distribution of SERPINB9 and gzmB predominantly overlaps. In cases in which they do not overlap, it is likely that the presence of SERPINB9 in bystander cells protects against tissue damage caused by gzmB released by CLs.…”

Granzymes in cancer and immunity

“…17 Furthermore, keratinocytes have been shown to express granzyme B and perforin on irradiation, with UVB-treated keratinocytes acquiring cytotoxicity toward various transformed cell lines in a perforin/granzyme B-dependent manner. 92 Recently, primary B cells were found to secrete active granzyme B, but not perforin or granzyme A, in the presence of IL-21 after B-cell receptor stimulation with either viral antigens or activating antibodies. 11 B cells from patients previously vaccinated against certain viruses produced more granzyme B when subsequently challenged with specific viral antigen, whereas granzyme B-expressing B cells lived longer and were more active than nongranzyme B-expressing memory B cells.…”