Localized External Beam Radiation Therapy (EBRT) to the Pelvis Induces Systemic IL-1Beta and TNF-Alpha Production: Role of the TNF-Alpha Signaling in EBRT-Induced Fatigue

• Published in: Radiation research 2016-01, Vol.185 (1), p.4-12
• Main Authors: McDonald, Tasha L., Hung, Arthur Y., Thomas, Charles R., Wood, Lisa J.
• Format: Article
• Language: English
• Subjects: Animals; Beams (radiation); Behavior, Animal - radiation effects; Body weight; Body Weight - radiation effects; Cancer; Eating - radiation effects; Fatigue; Fatigue (materials); Fatigue - etiology; Fatigue - physiopathology; Interleukin-1beta - blood; Irradiation; Male; Males; Mice; Mice, Inbred C57BL; Pelvis; Pelvis - radiation effects; Prostate; Prostate cancer; Prostatic Neoplasms - complications; Prostatic Neoplasms - radiotherapy; Quality of life; Radiation Injuries - etiology; Radiation Injuries - physiopathology; Radiation therapy; Radiotherapy Dosage; Radiotherapy, Conformal - adverse effects; REGULAR ARTICLES; Sicknesses; Signal Transduction - radiation effects; Space life sciences; Treatment Outcome; Tumor Necrosis Factor-alpha - blood
• ISSN: 0033-7587; 1938-5404
• DOI: 10.1667/RR14072.1

Prostate cancer patients undergoing localized external beam radiation therapy (EBRT) can experience a progressive increase in fatigue, which can affect physical functioning and quality of life. The purpose of this study was to develop a mouse EBRT prostate cancer treatment model with which to determine the role of pro-inflammatory cytokines in the genesis of EBRT-related fatigue. We assessed voluntary wheel-running activity (VWRA) as a proxy for fatigue, food intake and body weight in male C57BL/6 mice undergoing EBRT to the pelvis. In the first experiment, anesthetized male C57BL/6 mice underwent fractionated EBRT to the pelvis for a total dose of 68.2 Gy, thereby mimicking a clinically relevant therapeutic dose and frequency. The day after the last treatment, levels of IL-1β and TNF-α in plasma along with mRNA levels in liver, colon and whole brain were measured. EBRT-induced fatigue resulted in reduced body weight, diminished food intake, and increased plasma and tissue levels of IL-1β and TNF-α. In a follow-up experiment, we used TNF-α-deficient mice to further delineate the role of TNF-α signaling in EBRT-induced sickness behavior. EBRT-induced changes in fatigue, food intake and body weight were no different between TNF-α deficient mice and their wild-type counterparts. Taken together our data demonstrate that a clinically relevant localized irradiation of the pelvis induces a systemic IL-1β and TNF-α response and sickness behavior in mice, but the TNF-α signaling pathway alone does not independently mediate these effects.