Mizoribine selectively attenuates monocyte chemoattractant protein-1 production in cultured human glomerular mesangial cell: A possible benefit of its use in the treatment of lupus nephritis

Abstract

Mizoribine (MZR) is a selective inhibitor of the inosine monophosphate dehydrogenase - a key enzyme in the de novo pathway of guanine nucleotides - that was developed in Japan. Besides its immunosuppressive effects, MZR has recently been reported to suppress the progression of histologic chronicity via suppression of macrophage infiltration of the interstitium in selected patients with lupus nephritis. We examine the direct effect of MZR in human mesangial cells on the expression of functional molecules including monocyte chemoattractants in cultured human mesangial cells (MCs) treated with polyinosinic-polycytidylic acid (poly IC), a synthetic analogue of viral dsRNA, that makes 'pseudoviral' infection, and analyzed the expression of target molecules by reverse transcriptase-polymerase chain reaction and Western blotting. Thereafter, the effect of MZR on the expressions was examined. Pretreatment of cells with MZR partially, but significantly, attenuates the expression of monocyte chemoattractant protein (MCP)-1 mRNA and protein, whereas the poly IC-induced expressions for the other functional molecules, such as CCL5, fractalkine and IL-8 were not influenced by MZR treatment. On the other hand, pretreatment of cells with tacrolimus did not suppress the expression of MCP-1 mRNA. Mizoribine itself selectively attenuated the expression of MCP-1 both mRNA and protein levels in MCs treated with poly IC; that is, a possible model of 'pseudoviral' infection, which may be involved in the pathogenesis of lupus nephritis.