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

Abstract

Systemic administration of the bacterial endotoxin lipopolysaccharide (LPS) has profound depressive effects on behavior that are mediated by the inducible expression of pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-6 and tumor necrosis factor ␣ (TNF), in the brain. To assess the regulatory effects of the anti-inflammatory cytokine IL-4 on LPS-induced sickness behavior, rats injected intra-peritoneally (i.p.) with LPS were administered intracerebroventricularly (i.c.v.) with When an organism becomes sick during the course of an infection, several changes occur, which are mediated by the central nervous system (CNS). These changes include regulated increases in body temperature, sleep, activation of the hypothalamo-pituitary-adrenocortical (HPA) axis, decreases in locomotor activity, feeding, drinking, and social interactions, and alterations in brain neurotransmitters. 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). LPS induces the expression of not only pro-inflammatory but also anti-inflammatory cytokines such as IL-10 and IL-13 in the brain (Wong et al. 1997 Laman et al. 1998;Liedtke et al. 1998; Woodroofe and Cuzner 1993). Anti-inflammatory cytokines have the ability to suppress the synthesis of IL-1, TNF, and other cytokines in peripheral immune and non-immune cells (Dinarello 1997;Marie and Cavaillon 1997).There has been a recent surge of interest in the behavioral effects of cytokines in neuropsychopharmacology. Several reasons account for that, including the fact that cytokine-induced sickness behavior is not the result of weakness and physical debilitation but appears to be the expression of a previously unrecognized motivational state that is triggered by peripheral immune stimuli and reorganizes the organism's priorities (Dantzer 2001). In addition, the possibility of an intersection between sickness behavior and depression has raised new and important issues in psychopathology.If sickness behavior is the ineluctable result of the brain action of those proinflammatory cytokines that are released at the periphery during the course of an innate immune response or even in response to exteroceptive stressors, it becomes important to find out how this behavior is regulated. The production and ac...

Phenotypic Polarization of Activated Astrocytes: The Critical Role of Lipocalin-2 in the Classical Inflammatory Activation of Astrocytes

“…IL-4 appears to inhibit the classical activation of astrocytes in vivo. In our neuroinflammation model, pretreatment with IL-4 abolished LPS-induced gene expression and improved motor impairment in vivo, which is in line with previous findings that IL-4 attenuated LPS-induced proinflammatory cytokines and sickness behaviors (51). Therefore, classical or alternative activation stimuli seem to induce respective phenotypic changes and inhibit opposite phenotypes in astrocytes.…”

Inhibition of vagally mediated immune-to-brain signaling by vanadyl sulfate speeds recovery from sickness

“…1 A shows that IGF-1 administered peripherally improved recovery from LPS-induced sickness in wild-type but not in db͞db mice. Previous studies by us (57)(58)(59)(60) have shown that the antiinflammatory cytokines IL-1RA and IL-10 can down-regulate sickness, but these have all been administered i.c.v. Equally important is that db͞db mice were resistant to the sicknessimproving features of IGF-1 (Fig.…”

Type 2 Diabetes Impairs Insulin Receptor Substrate-2-Mediated Phosphatidylinositol 3-Kinase Activity in Primary Macrophages to Induce a State of Cytokine Resistance to IL-4 in Association with Overexpression of Suppressor of Cytokine Signaling-3

“…After 30 min, nonadherent cells were removed by washing twice with growth medium. Remaining cells were at least 80% macrophages confirmed by CD11b staining and morphology (50).…”