Medium-mediated bystander response after ionizing radiation is correlated with the increase of specific cytokines in human fibroblasts

For years research concerning radiation-induced damage initiated from the reasoning that in order for cells to experience malignant effects of ionizing radiation, direct contact of specific targets (DNA, RNA,..) with the radiation itself or with short-lived free radicals is required. It is becoming increasingly clear however, that cells experience a plethora of influences that are not solely restricted to close proximity effects. Apart from direct damage in target cells, ionizing radiation can invoke secondary effects in non-targeted cells. These secondary effects, collectively referred to as bystander effects, rely on communication between cells. Regarding this communication, two non-exclusive and probably complementary mechanisms have been proposed: direct cell-cell contact via gap junctions and secondly through secretion of small signaling components into the medium [1, 2]. We investigated the medium-mediated bystander response in human dermal fibroblasts (HDF) after exposure to ionizing irradiation. We looked at histone modifications, more specifically phosphorylation of H2AX. When a double stranded break (DSB) occurs H2AX is phosphorylated within minutes acting as a signal enhancer molecule in the DSB repair cascade. We showed that HDF experienced an elevated level of double stranded DNA damage repair foci, when incubated with conditioned growth medium of irradiated cells. The magnitude of this response is much lower than that of directly irradiated cells and is proportional to the irradiation dose. Using multiplex analysis, four cytokines IL-6, IL-8, MCP-1 and RANTES were identified in the growth medium of irradiated cells that were significantly upregulated and each with differential kinetics. These soluble proteins could function as potential bystander signaling mediators providing new insights to the complex domain of (in-)direct radiation biology. [1] M.V.Sokolov, J.S.Dickey, W.M.Bonner, O.A.Sedelnikova. gamma-H2AX in bystander cells: not just a radiation-triggered event, a cellular response to stress mediated by intercellular communication, Cell Cycle 6 (2007) 2210-2212. [2] H.Yang, N.Asaad, K.D.Held. Medium-mediated intercellular communication is involved in bystander responses of X-ray-irradiated normal human fibroblasts, Oncogene 24 (2005) 2096-2103.

Publication year:2009