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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Infection of Mu-sensitive bacteria with a recombinant lambda phage that carries the EcoRI.C fragment from the immunity end of wild type Mu DNA causes filamentous growth. Transmission electron microscopy revealed that the cell-division cycle was inhibited at, or prior to, the initiation of septation. The filamentation does not occur after infection of Mu-immune bacteria or after infection with a phage carrying the same EcoRI.C fragment, but with an IS1 insertion in gene B of Mu, showing that either gpB and/or some non-essential functions (e.g. kil) mapping downstream from the insertion are required for the inhibition of cell division. These data and previously published evidence suggest that in the "killing" of E. coli K12 by early Mu functions expressed from the cloned EcoRI.C fragment, two components have to be distinguished: one, a highly efficient elimination of plasmid DNA carrying the early Mu genes, and second, a series of interactions with host functions conducent to an inhibition of cell division. It is suggested that functions normally involved in the SOS reaction participate in the inhibition of cell division by early Mu functions. Infected bacteria synthesize the replication protein B (MR 33000) of Mu, which was found by cell fractionation experiments to be associated with the inner cell membrane. The role of this association for filamentous growth and for the integrative replication of the phage is discussed. The recombinant phage might be useful as a tool for the study of the E. coli cell division cycle.

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Recent evidence indicates that cytokines are potent inducers of nerve growth factor (NGF) expression in peripheral tissues and in brain. Cultured rat glomerular mesangial cells respond to interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) by increased NGF synthesis. We found that co-stimulation of rat glomerular mesangial cells with platelet-derived growth factor (PGDF-BB) and IL-1 beta/TNF-alpha significantly augments the IL-1 beta/TNF-alpha-induced NGF mRNA levels and NGF synthesis. In contrast, preincubation with PDGF-BB drastically reduces NGF gene expression and NGF protein synthesis in response to IL-1 beta/TNF-alpha stimulation. Thus our results indicate that PDGF-BB is a potent modulator of cytokine-induced NGF expression; its precise action is critically depending on the time at which the PDGF receptor is activated.