Expression of ras oncogenes in cultured human cells alters the transcriptional and posttranscriptional regulation of cytokine genes.

Autonomous production of cytokines such as the hematopoietic colony-stimulating factors (CSFs), IL-1, or IL-6 has been demonstrated in numerous human and murine neoplasms, and may be involved in the pathogenesis of several paraneoplastic syndromes such as leukocytosis, fever, and hypercalcemia. Because of the high frequency with which mutations in ras protooncogenes have been detected in human tumors, as well as evidence linking ras gene products to activation of certain cellular functions, we investigated whether ras mutations might influence the regulation of cytokine genes. Normal human fibroblasts transfected with a mutant val12 H-ras oncogene expressed increased levels of mRNA transcripts encoding granulocyte-CSF (G-CSF), granulocyte-macrophage-CSF (GM-CSF), and IL-1 beta compared with controls. Human mesothelioma cells transfected with a mutant asp12 N-ras oncogene exhibited similar alterations in cytokine gene expression. Estimates of transcriptional activity by nuclear run-on analysis revealed a selective increase in transcription only for the IL-1 gene. Analysis of mRNA half-life demonstrated a marked increase in the stability of numerous cytokine transcripts, including G-CSF, GM-CSF, IL-1, and IL-6. The addition of anti-IL-1 neutralizing antibody to cultures of cells expressing ras mutants did not block the expression of any of the cytokines examined, suggesting that the baseline expression of GM-CSF, G-CSF, and IL-6 was not a secondary event due to the increased transcription of IL-1. These results indicate that mutations in ras genes may alter expression of several cytokine genes through both transcriptional and posttranscriptional mechanisms.

Herniated intervertebral discs associated with unstable spinal injuries.

To examine the occurrence of traumatic herniated intervertebral discs associated with unstable spinal injuries, the authors reviewed the records of all patients with spinal cord level unstable spine injuries managed at their institution over a 26-month period. Ninety-three patients were identified. All patients had roentgenographic and computed tomographic (CT) evaluation. Magnetic resonance imaging was performed in 48 patients, and revealed the presence of a herniated intervertebral disc in 16, with the highest incidence being in the cervical spine. In the patients who had only plain film and CT scans, no disc pathology was identified. Magnetic resonance imaging provides a noninvasive means of examining intervertebral disc damage in unstable spinal injuries that might otherwise be unidentified and result in spinal cord injury at the time of surgery.