Caffeine promotes anti-tumor immune response during tumor initiation: Involvement of the adenosine A2A receptor.

Epidemiologic studies depict a negative correlation between caffeine consumption and incidence of tumors in humans. The main pharmacological effects of caffeine are mediated by antagonism of the adenosine receptor, A2AR. Here, we examine whether the targeting of A2AR by caffeine plays a role in anti-tumor immunity. In particular, the effects of caffeine are studied in wild-type and A2AR knockout (A2AR(-/-)) mice. Tumor induction was achieved using the carcinogen 3-methylcholanthrene (3-MCA). Alternatively, tumor cells, comprised of 3-MCA-induced transformed cells or B16 melanoma cells, were inoculated into animal footpads. Cytokine release was determined in a mixed lymphocyte tumor reaction (MLTR). According to our findings, caffeine-consuming mice (0.1% in water) developed tumors at a lower rate compared to water-consuming mice (14% vs. 53%, respectively, p=0.0286, n=15/group). Within the caffeine-consuming mice, tumor-free mice displayed signs of autoimmune alopecia and pronounced leukocyte recruitment intocarcinogen injection sites. Similarly, A2AR(-/-) mice exhibited reduced rates of 3-MCA-induced tumors. In tumor inoculation studies, caffeine treatment resulted in inhibition of tumor growth and elevation in proinflammatory cytokine release over water-consuming mice, as depicted by MLTR. Addition of the adenosine receptor agonist, NECA, to MLTR resulted in a sharp decrease in IFNγ levels; this was reversed by the highly selective A2AR antagonist, ZM241385. Thus, immune response modulation through either caffeine or genetic deletion of A2AR leads to a Th1 immune profile and suppression of carcinogen-induced tumorigenesis. Taken together, our data suggest that the use of pharmacologic A2AR antagonists may hold therapeutic potential in diminishing the rate of cancer development.

Sporadic culture-negative peritonitis in peritoneal dialysis patients--absence of endotoxin in dialysate.

BACKGROUND: Indiscriminate use of broad-spectrum antibiotics in peritonitis may have either unwanted side effects or contribute to the development of antibiotic resistance. It is tempting to use broad-spectrum antibiotics in cases of culture-negative peritonitis. This study examines whether Gram-negative agents have to be considered in the management of culture-negative peritonitis. Gram-negative agents are manifested by endotoxin easily detected by the Limulus amebocyte lysate (LAL) test. METHODS: 138 episodes of Gram-negative and culture-negative peritonitis have been retrospectively analyzed; episodes of Gram-negative peritonitis were controls. Correlation between LAL and culture results was compared between the two groups. The LAL test was performed using a commercial kit by incubating a mixture of dialysate effluent and LAL reagent at 37 degrees C. Development of a stable solid clot was considered positive. RESULTS: In controls, 80 out of 117 Gram-negative peritonitis were LAL positive (68%). None of the 21 culture-negative episodes was LAL positive. In 7 recurrences of Gram-negative peritonitis, the LAL test turned from negative to positive but in none of the recurrences of culture-negative peritonitis. The difference in correlation was highly significant. CONCLUSIONS: Gram-negative organisms do not seem to be involved in sporadic culture-negative peritonitis. In episodes of peritonitis in which bacteriologic cultures stay negative for 48 h, initial coverage of Gram-negative organisms may be dropped.