Exogenous Nitric Oxide Inhibits Tumor Necrosis Factor-Alpha- or Interleukin-1-Beta-Induced Monocyte Chemoattractant Protein-1 Expression in Human Mesangial Cells

Recent evidence indicates that cytokines are potent inducers of nerve growth factor (NGF) expression both in peripheral tissues and the central nervous system and that NGF, in addition to its neurotrophic action, also acts as an immunoregulatory agent. It was of interest to investigate whether inflammatory cytokines affect NGF production in renal mesangial cells, which play a crucial role in the modulation of the local immune function in the glomerulus. Our results show that the simultaneous addition of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) elicited a marked (13-fold) increase of NGF protein released by cultured rat glomerular mesangial cells within 24 h, whereas IL-1 alpha in combination with TNF-alpha, as well as the cytokines alone, did not promote the synthesis of NGF. The synergistic effect was dose dependent (maximal at 1 nM) and due to enhanced gene expression, since the cytokine treatment caused a fivefold increase in NGF mRNA after 8 h. Stimulation of NGF synthesis was abolished by mepacrine and dexamethasone, indicating that phospholipase A2 may be involved in NGF regulation. Moreover, pretreatment of the cells with the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) abolished induction of NGF by cytokines; in contrast, the specific cyclooxygenase inhibitors indomethacin and diclofenac failed to modify NGF production. These data suggest that a lipoxygenase metabolite produced in response to IL-1 beta and TNF-alpha acts as a mediator in NGF gene expression. In conclusion, these findings support a model in which a cytokine cascade including NGF may play an important role in the pathophysiology of inflammatory renal diseases.

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Differential effects of cytokines on thermosensitive neurons in guinea pig preoptic area slices

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1991.261.5.r1096 ◽

1991 ◽

Vol 261 (5) ◽

pp. R1096-R1103 ◽

Cited By ~ 5

Author(s):

M. Shibata ◽

C. M. Blatteis

Keyword(s):

Guinea Pig ◽

Preoptic Area ◽

Interleukin 1 ◽

Interleukin 1 Beta ◽

Necrosis Factor Alpha ◽

Firing Rates ◽

Artificial Cerebrospinal Fluid ◽

Cold Sensitive ◽

Factor Alpha ◽

Necrosis Factor

This study was undertaken to determine whether the reported different courses of the febrile responses to the cytokines interleukin-1 beta (IL-1), interferon-alpha 2 (IFN), and tumor necrosis factor-alpha (TNF) might have neuroelectrophysiological correlates. The reactions of individual thermosensitive neurons in the preoptic area (POA) were evaluated by recording their extracellular single-unit firing rates (FR) in slices of guinea pig POA perfused with artificial cerebrospinal fluid (aCSF), human recombinant IL-1 (50-500 ng), IFN (1,000-8,000 U), and TNF (400-5,000 ng) (all doses per min/ml aCSF); thermosensitivity was assessed by FR responses to changes of perfusate temperature (32-42 degrees C). Overall, these cytokines depressed the FR of warm-sensitive units and excited those of cold-sensitive units, in agreement with expectations. However, the responses of individual neurons treated with two or all three cytokines were dissimilar: 61% of the units tested reacted differentially to two or three cytokines, 32% exhibited identical responses, and 7% had no response to any cytokine. These results support the possibility that IL-1, IFN, and TNF may affect not the same but rather distinct neurons functionally connected to common pyrogenic effectors. Thus they suggest that differential neuronal substrates may be utilized by each cytokine to exert its pyrogenic effect.

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