Dexamethasone prevents autoimmune nephritis and reduces renal expression of Ia but not costimulatory signals (original) (raw)

. 1992 Sep;141(3):743–751.

Abstract

Although glucocorticoids are a conventional treatment for lupus nephritis, the cellular and molecular mechanisms responsible for preventing renal injury are unknown. MRL-lpr mice develop an aggressive autoimmune nephritis. As these mice become nephritic, there is an increase in the renal expression of molecules that permit or facilitate immune interactions, including MHC class II (Ia) antigens, intercellular adhesion molecule-1 (ICAM-1), and pro-inflammatory cytokines. Because dexamethasone (Dex) alters Ia antigen expression and suppresses cytokine generation, the authors prophylactically treated MRL-lpr mice and investigated the relative importance of these molecules in inducing renal injury. MRL-lpr mice given Dex (0.4 mg/kg/d) from age 6 weeks were killed 4, 8, and 16 weeks after the initiation of therapy, and tissue was removed for histology and extraction of total RNA. Dex prevented lymphadenopathy and renal injury. DEX eliminated the marked Thy 1.2+ lymphocytic infiltrates within the kidney and preserved normal renal histology and urinary protein levels. Northern blot analysis of steady-state mRNA transcripts indicated Dex suppressed a four-fold increase in kidney major histo-compatibility complex class II (Ia) molecule antigen mRNA seen by age 22 weeks (Ia/beta-actin ratios = 0.64 +/- 0.50 versus 2.32 +/- 0.48, P less than 0.01), but did not alter the costimulatory molecules ICAM-1 or tumor necrosis factor alpha (TNF alpha). Although all of these molecules are important mediators of inflammation, autoimmune nephritis was ameliorated without alteration of TNF alpha gene transcription or ICAM-1 transcription and surface expression. This study suggests that the benefit of steroids in nephritis stems from preventing lymphocyte infiltration into the kidney and decreasing immune interactions by limiting Ia expression.

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