The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle
Fabio Benigni, … , Tina Peng, Richard Bucala
Fabio Benigni, … , Tina Peng, Richard Bucala
Published November 15, 2000
Citation Information: J Clin Invest. 2000;106(10):1291-1300. https://doi.org/10.1172/JCI9900.
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Article

The proinflammatory mediator macrophage migration inhibitory factor induces glucose catabolism in muscle

Abstract

Severe infection or tissue invasion can provoke a catabolic response, leading to severe metabolic derangement, cachexia, and even death. Macrophage migration inhibitory factor (MIF) is an important regulator of the host response to infection. Released by various immune cells and by the anterior pituitary gland, MIF plays a critical role in the systemic inflammatory response by counterregulating the inhibitory effect of glucocorticoids on immune-cell activation and proinflammatory cytokine production. We describe herein an unexpected role for MIF in the regulation of glycolysis. The addition of MIF to differentiated L6 rat myotubes increased synthesis of fructose 2,6-bisphosphate (F2,6BP), a positive allosteric regulator of glycolysis. Increased expression of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) enhanced F2,6BP production and, consequently, cellular lactate production. The catabolic effect of TNF-α on myotubes was mediated by MIF, which served as an autocrine stimulus for F2,6BP production. TNF-α administered to mice decreased serum glucose levels and increased muscle F2,6BP levels; pretreatment with a neutralizing anti-MIF mAb completely inhibited these effects. Anti-MIF also prevented hypoglycemia and increased muscle F2,6BP levels in TNF-α–knockout mice that were administered LPS, supporting the intrinsic contribution of MIF to these inflammation-induced metabolic changes. Taken together with the recent finding that MIF is a positive, autocrine stimulator of insulin release, these data suggest an important role for MIF in the control of host glucose disposal and carbohydrate metabolism.

Authors

Fabio Benigni, Toshiya Atsumi, Thierry Calandra, Christine Metz, Bernd Echtenacher, Tina Peng, Richard Bucala

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Figure 1

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(a) Intracellular F2,6BP levels in L6 myotubes. Fully differentiated L6 ...
(a) Intracellular F2,6BP levels in L6 myotubes. Fully differentiated L6 muscle cells were stimulated with TNF-α (100 ng/ml) or MIF (1–100 ng/ml) for 72 hours at 37°C. Lysates were prepared and analyzed for F2,6BP content as described in Methods. Data are expressed as mean ± SD (AP < 0.05 versus control medium) of triplicate wells and are representative of three independently performed experiments. (b) Induction of rat muscle PFK-2 expression by TNF-α or MIF in L6 muscle cells, as detected by RT-PCR analysis using gene-specific primers. The amplification cycle number was varied initially in order to establish a linear amplification response, as assessed by laser densitometric analysis. (c) Lactate production by L6 myotubes. Differentiated L6 muscle cells (1.4 × 106 cells per well) were stimulated with either TNF-α or MIF (each at 100 ng/ml). Supernatants were collected at 24 and 72 hours after stimulation, and the lactate levels were measured. Data are expressed as mean ± SD (AP < 0.05 versus control medium) of triplicate wells and are representative of three independently performed experiments.