ANTISENSE DOWN-REGULATION OF METALLOTHIONEIN IN A HUMAN MONOCYTIC CELL-LINE ALTERS ADHERENCE, INVASION, AND THE RESPIRATORY BURST

A human monocyte-derived cell line (THP-1) was used as a model to inve stigate the role of metallothionein (MT) in the cellular physiology of resting and activated monocytes. MT protein levels were reduced in TH P-1 cells by transient transfections with an antisense MT expression v ector. Antisense mouse MT-1 RNA was constitutively expressed under the control of the H-2K(b) (mouse major histocompatibility complex I) pro moter and could be further induced by lipopolysaccharide (LPS) treatme nt. THP-1 cells expressing antisense MT RNA (aMT-THP-1) had a 30% redu ction in MT protein levels. In the absence of LPS treatment, aMT-THP-1 cells demonstrated increased production of H2O2 concurrent with enhan ced adherence and invasiveness compared to cells transfected with the control vector (cv-THP-1). Treatment of aMT-THP-1 cells with LPS depre ssed these activation-associated responses and further reduced the lev el of MT protein. cv-THP-1 cells activated by LPS produced high levels of H2O2 and adhered to and invaded a reconstituted basement membrane. In addition to increasing cadmium sensitivity, diminished MT levels a ffected broad-ranging processes associated with resting and activated monocyte function. Thus, metallothionein plays an important physiologi cal role in cells in addition to its role in detoxification of heavy m etals.