The physiological roles of extracellular metallothionein.

Metallothionein (MT) is a low-molecular-weight protein with a number of roles to play in cellular homeostasis. MT is synthesized as a consequence of a variety of cellular stressors, and has been found in both intracellular compartments and in extracellular spaces. The intracellular pool of this cysteine-rich protein can act as a reservoir of essential heavy metals, as a scavenger of reactive oxygen and nitrogen species, as an antagonist of toxic metals and organic molecules, and as a regulator of transcription factor activity. The presence of MT outside of cells due to the influence of stressors suggests that this protein may make important contributions as a "danger signal" that influences the management of responses to cellular damage. While conventional wisdom has held that extracellular MT is the result of cell death or leakage from stressed cells, there are numerous examples of selective release of proteins by nontraditional mechanisms, including stress response proteins. This suggests that MT may similarly be selectively released, and that the pool of extracellular MT represents an important regulator of various cellular functions. For example, extracellular MT has effects both on the severity of autoimmune disease, and on the development of adaptive immune functions. Extracellular MT may operate as a chemotactic factor that governs the trafficking of inflammatory cells that move to resolve damaged tissues, as a counter to extracellular oxidant-mediated damage, and as a signal that influences the functional behavior of wounded cells. A thorough understanding of the mechanisms of MT release from cells, the conditions under which MT is released to the extracellular environment, and the ways in which MT interacts with sensitive cells may both illuminate our understanding of an important control mechanism that operates in stressful conditions, and should indicate new opportunities for therapeutic management via the manipulation of this pool of extracellular MT.