DYSREGULATION OF CYTOKINE EXPRESSION IN TUBULOINTERSTITIAL NEPHRITIS ASSOCIATED WITH MURINE MALARIA

We examined the circulating levels of the proinflammatory cytokines tu mor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1 alpha, IL-6, granulocyte macrophage-colony stimulating factor (GM-CSF), and the an ti-inflammatory cytokine IL-10, and their expression in kidneys acutel y infected with murine malaria parasite P. berghei ANKA in C57BL/6J mi ce. Groups of six mice sacrified on days 5, 10, 15, and 20, and normal controls were used for cytokine analysis. High concentrations of TNF- alpha and IL-10 were detected in plasma as shown by ELISA, and elevate d levels of mRNA specific for TNF-alpha and IL-10 in infected kidneys were demonstrated by reverse transcription-polymerase chain reaction ( RT-PCR) analysis. Kidney sections stained with antibodies against TNF- alpha, IL-1 alpha, IL-6, GM-CSF and IL-10 for immunohistochemistry sho wed markedly enhanced staining for TNF-alpha, and progressively increa sed staining for IL-1 alpha and IL-6 both in the tubules and the walls of arteries during the course of infection. The endothelia of blood v essels and inflammatory cells located around small arteries showed pos itive staining for GM-CSF from day 10 onwards. Unlike the staining for proinflammatory cytokines, the anti-inflammatory cytokine IL-10 showe d strongly positive staining in normal tubules and walls of arteries, especially in the brush border of proximal tubules, but the staining i ntensity decreased dramatically after day 15 post-infection. A strongl y positive correlation was found between the antibody staining for TNF -alpha/IL-1 alpha in tubules, and the severity of proteinuria. In cont rast, there was an inverse correlation between the staining for IL-10 with TNF-alpha/IL-1 alpha, and the degree of proteinuria. Plenty of pi gmented macrophages showed positive staining both for proinflammatory and anti-inflammatory cytokines in the tubulointerstitium. Our finding s imply that the up-regulation of proinflammatory cytokines and the dy sregulation of anti-inflammatory cytokines are involved in the pathoge nesis of tubulointerstitial nephritis associated with malaria.