MURINE TUMOR-NECROSIS-FACTOR-ALPHA IS TRANSPORTED FROM BLOOD TO BRAIN IN THE MOUSE

The cytokines are important components of the brain-immune axis. Recent work has shown that [I-125]IL-1alpha and [I-125]IL-1beta are transported from the blood into the brain by a saturable system. Here we show that murine tumor necrosis factor alpha (mTNFalpha) labeled with I-125 (I-mTNFalpha) crosses the blood-brain barrier (BBB) after i.v. injection by a transport system different from that for the interleukins. Self inhibition with mTNFalpha showed that this transport system was saturable, and lack of inhibition by IL-1alpha, IL-1beta, IL-6, or MIP-1alpha showed selectivity of the system. High performance liquid chromatography (HPLC) of the radioactivity recovered from brain and from cerebrospinal fluid after the iv. injection of 1-mTNFalpha showed that the cytokine crossed the BBB largely in intact form. Capillary depletion showed that the accumulation of I-mTNFalpha in the cerebral cortex was due to passage across the BBB rather than to sequestration by capillaries. Transport rate was not changed by acute treatment with the neurotoxin aluminium or by acute and chronic treatment with the cationic chelator deferoxamine, but it was more than three times faster in neonatal rats. Efflux of I-mTNFalpha from the brain was slower than would have been predicted based on reabsorption of cerebrospinal fluid, suggesting that TNFalpha is sequestered by the brain. The BBB was not disrupted by up to 50 mug kg-1 of mTNFalpha i.v. in either adult mice or neonatal rats as assessed by the BBB's impermeability to radioactively labeled albumin. The saturable transport of mTNFalpha across the BBB supports the concept of direct blood to brain transport of cytokines as a mechanism by which the peripheral immune system can affect brain function.