Administration of TNF-a, IL-ip, or IL-18 increases the length of NREM sleep time and decreases the duration of REM sleep. Patients treated with recombinant or purified cytokines for specific forms of cancers or viral infections such as hepatitis B or C become somnolent (Papanicolaou, Wilder, Manolagas, and Chrousos 1998).
IL-1 and TNF-a have been shown to be somnogenic in every species thus far tested (e.g., mice, rats, cats, monkeys, and rabbits) and are effective whether given directly into the brain or after intraperitoneal or intravenous injections. On the other hand, the effect of cytokine administration is dependent not only on the mood and time of administration but also on the dosage. For instance, IL-1 and TNF-a appear to induce physiological sleep, however, high doses of IL-1 rather inhibit than promote sleep. Rabbits given IL-1 at dark onset sleep about 3 extra hours during the first 12 h after the injection but normal sleep patterns are maintained. Administration of TNF-a or IL-1P also increases the amplitude of slow wave EEG, while that of IL-10 and IL-4, inhibits NREM (Krueger et al. 2001).
The administration of cytokines results in pleitropic action in the CNS, e.g., IFN-y, IL-1P, and TNF-a have not only somnogenic but also lethargic, pyrogenic, and anorectic effects (Rothwell 1997; Sternberg 1997). These effects are dose-dependent, i.e., both IL-1 and TNF-a induce increased NREMS at doses lower than those needed to induce fever. At slightly higher doses they are both somnogenic and pyrogenic, however, these actions can be separated by coadministration of an antipyretic that blocks IL-1-induced fever but not IL-1-induced NREMS (Krueger, Walter, Dinarello, Wolff, and Chedid 1984).
IL-2 that is also used as a therapeutic agent for treatment of various forms of cancer has been shown to produce partial remission in some patients with renal cell carcinoma or metastatic melanoma. It has also some neuropsychiatric side effects corresponding to symptoms associated with depression, such as fatigue, increased sleepiness and difficulty sleeping, irritability, anorexia, weight loss, and apathy (Krigel et al. 1990; Collier and Chapman 2001).
Cytokines are also used in combination in cancer therapy. For instance, IL-2 is administered in combination with IFN-a in order to increase the response rate. Although many studies agree that depression is worsened during immunotherapy, there are many differences in the prevalence of these side effects (Mulder, Ang, Chapman, Ross, Stevens, and Edgar, 2000; Musselman et al. 2001). The possible explanation for the discrepancies might be that neuropsychiatric side effects appear to be dose-related (Denicoff et al. 1987; Dusheiko 1997). In addition, the duration of therapy may also influence the occurrence of sleep disturbances.
Although the exact mechanisms of the somnogenic or antisomnogenic effects of cytokines have not yet been fully elucidated, the cascade has also been shown to involve other factors, such as growth hormone-releasing hormone, corticotrophin-releasing hormone, nitric oxide synthase, prostaglandins, and components of signaling mechanisms leading to activation of the transcription nuclear factor kappa B (NF-kB) (Mills and Dimsdale 2004).
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