Phenolic compounds are numerous and ubiquitous in the plant kingdom, being particularly present in health-promoting foods. Epidemiological evidences suggest that the consumption of polyphenol-rich foods reduces the incidence of cancer, coronary heart disease and inflammation. Chlorogenic acid (CGA) is one of the most abundant polyphenol compounds in human diet. Data obtained from in vivo and in vitro experiments show that CGA mostly presents antioxidant and anti-carcinogenic activities. However, the effects of CGA on the inflammatory reaction and on the related pain and fever processes have been explored less so far. Therefore, this study was designed to evaluate the anti-inflammatory, antinociceptive and antipyretic activities of CGA in rats. In comparison to control, CGA at doses 50 and 100 mg/kg inhibited carrageenin-induced paw edema beginning at the 2nd hour of the experimental procedure. Furthermore, at doses 50 and 100 mg/kg CGA also inhibited the number of flinches in the late phase of formalin-induced pain test. Such activities may be derived from the inhibitory action of CGA in the peripheral synthesis/release of inflammatory mediators involved in these responses. On the other hand, even at the highest tested dose (200 mg/kg), CGA did not inhibit the febrile response induced by lipopolysaccharide (LPS) in rats. Additional experiments are necessary in order to clarify the true target for the anti-inflammatory and analgesic effects of CGA.

The immune and central nervous systems are functionally connected and interacting. The concept that the immune signaling to the brain which induces fever during infection and inflammation is mediated by circulating cytokines has been traditionally accepted. Administration of bacterial lipopolysaccharide (LPS) induces the appearance of a sotermed cytokine cascade in the circulation more or less concomitantly to the developing febrile response. Also, LPS-like fever can be induced by systemic administration of key cytokines (IL-1ß, TNF-a, and others). However, anti-cytokine strategies against IL-1ß or TNFa along with systemic injections of LPS frequently lead to attenuation of the later stages of the febrile response but not of the initial phase of fever, indicating that cytokines are rather involved in the maintenance than in the early induction of fever. Within the last years experimental evidence has accumulated indicating the existence of neural transport pathways of immune signals to the brain. Because subdiaphragmatic vagotomy prevents or attenuates fever in response to intraperitoneal or intravenous injections of LPS, a role for vagal afferent nerve fibers in fever induction has been proposed. Also other sensory nerves may participate in the manifestation of febrile responses under certain experimental conditions. Thus, injection of a small dose of LPS into an artificial subcutaneous chamber results in fever and formation of cytokines within the inflamed tissue around the site of injection. This febrile response can be blocked in part by injection of a local anesthetic into the subcutaneous chamber, indicating a participation of cutaneous afferent nerve signals in the manifestation of fever in this model. In conclusion, humoral signals and an inflammatory stimulation of afferent sensory nerves can participate in the generation and maintenance of a febrile response. Key wordsHumoral signals and fever: the relation between circulating cytokines and the febrile response After a challenge with an infectious or inflammatory stimulus somewhere at the periphery of the body a number of responses are generated within the CNS. These brainmediated signs of illness include changes in neuroendocrine activities including activation of the hypothalamic-pituitary-adrenal (HPA) axis, anorexia and adipsia, changes in

Several studies have now clearly established the ability of LPS to induce bradykinin B1 receptor up-regulation in vivo and the functional relevance of this up-regulation for the pathophysiological effects of LPS. Using an in vivo system in which LPS is injected locally into the rat paw, we have examined the potential contribution of proinflammatory cytokines, NF-κB activation, and neutrophil influx for the functional and molecular up-regulation of the bradykinin B1 receptor. Treatment with LPS resulted in a rapid and sustained functional up-regulation of B1 receptors in the rat paw that correlated with the increase in B1 receptor mRNA levels. B1 receptor up-regulation is preceded by the rapid activation of the transcription factor NF-κB and the production of proinflammatory cytokines, including TNF-α and IL-1β. More importantly, blockade of NF-κB translocation, TNF-α, or IL-1β prevented the functional and molecular up-regulation of B1 receptors. Injection of LPS also induced the influx of neutrophils that followed the peak of cytokine production and associated with the persistent activation of NF-κB and functional B1 receptor up-regulation. Blockade of neutrophil influx with platelet-activating factor receptor antagonists or cell adhesion molecule blockers prevented B1 receptor up-regulation. Thus, by acting in cooperation and in a coordinated, timely manner, TNF-α, IL-1β, neutrophils, and the transcription factor NF-κB are major and essential players in the ability of LPS to induce B1 receptor expression in vivo.

The effect of rat antimacrophage serum (rAMS) was tested on the influence of normal or thioglycollate-stimulated macrophage populations of the rat peritoneal cavity on the migration of polymorphonuclear neutrophils (PMN) induced by carrageenin, heterologous serum (rabbit) and sheep red blood cells. The rAMS used did not cross-react with PMN or lymphocytes nor did it affect circulating white cells, complement levels or lysed PMN present in the inflammatory exudate. It did, however, give a positive immunofluorescence reaction with resident and stimulated macrophages. The rAMS inhibited macrophage function as tested by sheep red blood cell phagocytosis in vivo and release of a PMN chemotactic factor(s) in vitro. Thioglycollate-stimulated peritoneal cavities showed an increased macrophage population and responded with increased PMN migration when challenged with heterologous serum or carrageenin, as compared with control rats. The presence of rat antimacrophage antibodies inhibited PMN migration induced by heterologous serum, sheep red blood cells and carrageenin. It is concluded that resident macrophages participate in the control of PMN migration to the site of an acute inflammation by acting as 'alarm cells' and triggering several defence mechanisms which ultimately protect the host from injurious stimuli.

The alpha and beta forms of recombinant interleukin-1 (IL-1 alpha and IL-1 beta) and of recombinant Tumor Necrosis Factor (TNF alpha and TNF beta) induced dose-dependent neutrophil migration into rat peritoneal cavities. Migration induced by both IL-1s showed a bell-shaped dose-response curve and IL-1 beta was 3-fold more potent than IL-1 alpha. Pretreatment of the animals with dexamethasone or depletion of the peritoneal macrophage population, abolished the neutrophil migration induced by the four cytokines. "In vitro" stimulation of macrophage monolayers with IL-1 beta and the TNFs released a factor into the supernatant which, unlike these cytokines, induced neutrophil migration in dexamethasone pretreated animals. These results suggest that the neutrophil migration induced by IL-1 alpha, IL-1 beta, TNF alpha and TNF beta is not due to a direct effect on neutrophils, but occurs via the release of a chemotactic factor(s) from resident macrophages.

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