Macrophage migration inhibitory factor induces cell death and decreases neuronal nitric oxide expression in spinal cord neurons

Macrophage migration inhibitory factor is a potent proinflammatory cytokine; however, its role in spinal cord injury is poorly understood. Therefore, the aim of the present study was to investigate the effects of macrophage migration inhibitory factor on spinal cord neuron survival and viability. Due to the importance of nitric oxide metabolism in these events, part of our study was also focused on the influence of recombinant macrophage migration inhibitory factor on neuronal nitric oxide expression. Exposure of cultured mouse spinal cord neurons to macrophage migration inhibitory factor markedly increased cellular oxidative stress as measured by 2′,7′-dichlorofluorescein fluorescence and intracellular calcium levels. In addition, an antagonist of the inositol 1,4,5-triphosphate receptor, 8-(diethylamino)octyl 3,4,5-trimethoxybenzoate, completely blocked the macrophage migration inhibitory factor-induced increase in intracellular calcium levels. Macrophage migration inhibitory factor treatment also decreased cell viability, increased cellular lactate dehydrogenase release, and induced chromatin condensation and aggregation in cultured spinal cord neurons. Finally, exposure to macrophage migration inhibitory factor markedly decreased expression and activity of neuronal nitric oxide, accompanied by a decrease in cellular guanosine 3′5′-cyclic monophosphate levels. The present results indicate that macrophage migration inhibitory factor can induce dysfunction of spinal cord neurons, leading to cell death through oxidative stress and intracellular calcium-dependent pathways

Involvement of nuclear factor-kappaB in macrophage migration inhibitory factor gene transcription up-regulation induced by interleukin- 1 beta in ectopic endometrial cells.

OBJECTIVE: To investigate the involvement of the nuclear factor (NF)-kappaB in the interleukin (IL)-1 beta-mediated macrophage migration inhibitory factor (MIF) gene activation. DESIGN: Prospective study. SETTING: Human reproduction research laboratory. PATIENT(S): Nine women with endometriotic lesions. INTERVENTION(S): Endometriotic lesions were obtained during laparoscopic surgery. MAIN OUTCOME MEASURE(S): The MIF protein secretion was analyzed by ELISA, MIF mRNA expression by quantitative real-time polymerase chain reaction (PCR), NF-kappaB translocation into the nucleus by electrophoresis mobility shift assay, I kappaB phosphorylation and degradation by Western blot, and human MIF promoter activity by transient cell transfection. RESULT(S): This study showed a significant dose-dependent increase of MIF protein secretion and mRNA expression, the NF-kappaB translocation into the nucleus, I kappaB phosphorylation, I kappaB degradation, and human MIF promoter activity in endometriotic stromal cells in response to IL-1 beta. Curcumin (NF-kappaB inhibitor) significantly inhibited all these IL-1 beta-mediated effects. Analysis of the activity of deletion constructs of the human MIF promoter and a computer search localized two putative regulatory elements corresponding to NF-kappaB binding sites at positions -2538/-2528 bp and -1389/-1380 bp. CONCLUSION(S): This study suggests the involvement of the nuclear transcription factor NF-kappaB in MIF gene activation in ectopic endometrial cells in response to IL-1 beta and identifies a possible pathway of endometriosis-associated inflammation and ectopic cell growth

Pneumatosis intestinalis in the setting of COVID-19: a single center case series from New York

This case series reviews four critically ill patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [coronavirus disease 2019 (COVID-19)] suffering from pneumatosis intestinalis (PI) during their hospital admission. All patients received the biological agent tocilizumab (TCZ), an interleukin (IL)-6 antagonist, as an experimental treatment for COVID-19 before developing PI. COVID-19 and TCZ have been independently linked to PI risk, yet the cause of this relationship is unknown and under speculation. PI is a rare condition, defined as the presence of gas in the intestinal wall, and although its pathogenesis is poorly understood, intestinal ischemia is one of its causative agents. Based on COVID-19's association with vasculopathic and ischemic insults, and IL-6's protective role in intestinal epithelial ischemia–reperfusion injury, an adverse synergistic association of COVID-19 and TCZ can be proposed in the setting of PI. To our knowledge, this is the first published, single center, case series of pneumatosis intestinalis in COVID-19 patients who received tocilizumab therapy