Fever induction pathways: evidence from responses to systemic or local cytokine formation

Abstract

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

Interleukin-1β induced activation of the hypothalamus–pituitary–adrenal axis is dependent on interleukin-1 receptors on non-hematopoietic cells

“…Moreover, blockage of neural signaling in somatic nerves by local anesthesia has been shown to abolish centrally elicited responses to peripheral immune challenge (Belevych et al, 2010;Roth and De Souza, 2001). Considering the findings in previous studies (Ching et al, 2007;Elander et al, 2009), it is hence conceivable that the c-Fos expression in the by such a direct neuronal route, whereas the activation that was seen after intravenous injection of IL-1β may be dependent on signaling across the blood-brain barrier.…”

Behavioral fever in ectothermic vertebrates

“…200 mg/kg, injected into the lymph sac (Bicego-Nahas et al, 2000); fish: 1000 mg/kg, injected intraperitoneally (Grans et al, 2012)) is 20e200 times higher than those effective to induce fever in rats (5 mg/kg, injected intravenously (Soares et al, 2009); 50 mg/kg, injected intraperitoneally (Tavares et al, 2006)) and guinea pigs (10 mg/kg, injected intra-arterially (Roth and de Souza, 2001)). …”

Dual Effect of Central Injection of Recombinant Rat Interleukin-4 on Lipopolysaccharide-Induced Sickness Behavior in Rats

“…They are due to the release of pro-inflammatory cytokines such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor-alpha (TNF-␣ ) by activated monocytes and macrophages Dinarello 2000;Gabay and Kushner 1999;Krueger et al 1999;Mulla and Buckingham 1999;Rothwell 1997;Turrin and Plata-Salaman 2000). The same effects can be obtained by systemic administration of the cytokine-inducer lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria (Cabrera et al 2000;Francis et al 2000;Lacosta et al 1999;Ma et al 2000;MohanKumar et al 2000;Roth and de Souza 2001;Swiergel and Dunn 1999;Yirmiya 1996;Yirmiya et al 2001). Peripherally released cytokines act on the brain by inducing the expression and release of cytokines in the central nervous system (Eriksson et al 2000;Konsman et al 1999;Layé et al 2000;Quan et al 2000).…”