Robert Dantzer

IL-1β-mediated innate immunity is amplified in the db/db mouse model of type 2 diabetes

Chronic inflammation appears to play a critical role in type 2 diabetes and its complications. Here we tested the hypothesis that this inflammatory dysregulation affects the IL-1β system and has functional consequences in the brain. Diabetic, db/db, and nondiabetic, db/+, mice were administered i.p. LPS, a potent cytokine inducer, at a dose of 100 μg/kg/mouse. db/db mouse innate immune-associated sickness behavior was 14.8, 33, 44.7, and 34% greater than that of db/+ mice at 2, 4, 8, and 12 h, respectively. When a fixed dose of LPS was used (5 μg/mouse), db/db mouse sickness was again enhanced 18.4, 22.2, and 14.5% at 4, 8, and 12 h as compared with db/+ mice. In diabetic mice, peritoneal macrophages produced more IL-1β in response to LPS, and peritoneal levels of IL-1β induced by LPS were increased. Importantly, IL-1R antagonist and type 2 IL-1 receptor (IL-1R2) failed to up-regulate in response to LPS in db/db mice. Finally, both peripheral and central administration of IL-1β, itself, induced sickness in db/db mice that mimicked the effects of peripheral LPS and was significantly greater than that seen in db/+ mice. Taken together, these results indicate that IL-1β-mediated innate immunity is augmented in db/db mice both at the periphery and in the brain, and the mechanism is due to diabetes-associated loss of IL-1β counterregulation.

Cytokine Actions on Behavior

Sickness behavior refers to a coordinated set of behavioral changes that develop in sick individuals during the course of an infection. These changes are due to the effects of proinflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α) on brain cellular targets and represent the expression of a well organized central motivational state. Based on the results of pharmacological and biochemical experiments, it is now apparent that sickness behavior is mediated by cytokines which are temporarily expressed in the brain in response to peripheral cytokines. Centrally released cytokines act on brain receptors which are identical to those characterized on immune cells. Primary afferent nerves represent the main communication pathway between peripheral and central cytokines. The sickness inducing effects of cytokines are downregulated by a number of endogenous neuropeptides and hormones, including vasopressin and glucocorticoids.

Mechanisms of action of cytokines on the central nervous system. Interaction with glucocorticoids

Interleukin-1 (IL-1), IL-6 and tumour necrosis factor-alpha (TNFα) are multifunctional cytokines which are released by activated monocytes and macrophages and play a pivotal role in inflammation and infection [1]. Although their biological activities widely overlap, each cytokine has its own characteristic properties. IL-1 exists in two molecular forms, IL-1α and IL-lβ, which are encoded by different genes. Another member of the IL-1 family is the interleukin-1 receptor antagonist (IL-lra). This cytokine behaves as a pure endogenous antagonist of IL-1 receptors and blocks most biological effects of IL-lα and IL-lβ in vivo and in vitro. IL-6 is mainly responsible for the synthesis of acute phase proteins by hepatocytes. TNFα plays a major role in the pathogenesis of the acute shock syndrome. Although all of these cytokines are produced mainly by activated monocytes and macrophages, they are also synthesized by a wide variety of immune and non-immune cells, including glia and neurons [2]. IL-1, IL-6 and TNFα have potent effects in the central nervous system, resulting in fever, induction of sickness behaviour, and activation of the hypothalamic-pituitary-adrenal (HPA) axis [3].

Polyunsaturated Fatty Acids and Neuro-Inflammation

Inflammation is an active defense reaction against diverse insults that aims at neutralizing noxious agents. Although inflammation serves a protective function in controlling infection and promoting tissue repair, it can also cause tissue damage. Inflammatory mediators include complement, adhesion molecules, products of cyclooxygenase (COX) enzymes, eicosanoids, and cytokines. Cytokines are polypeptides that are generally associated with inflammation, immune activation, and cell differentiation or death. They include interleukins (ILs), interferons (IFNs), tumor necrosis factors (TNFs), chemokines, and growth factors. Although most have little or no function in healthy tissues, they are rapidly induced locally in response to tissue injury, infection, or inflammation.

Heterogeneity of receptor mechanisms mediating the behavioural effects of interleukin-1

SEPARATION AND ISOLATION OF MYELOPEPTIDES WITH IMMUNeAND NEUROTROPIC ACTIVITIES A.A. Mikhailova, L.A. Fonina, e.G. Yanovsky Shemyakin Institute of Bioorganic Chemistry, USSR Academy of Sciences, Moscow, USSR Bone marrow cells of various species and man produce bioregulatory molecules (molecular mass 500 to 3,000 D) of the peptide nature myelopeptides (NIP). They are accumvlated in the supcmatant of the bone marrow cel! culture during short-time cultivation. The mixture of nonidentified MP isolated from the supornatant displays the biological activity of different types. MP induce the 2-3-fold enhancement in antibody form:tion; increase phagocytosis of macrophages and nourophils, correct some cengenetal and acquired defects of the immunity, elicit terminal differentiation of human leukemia cells of line HL-60. Along with immunotropic action MP show the clearly expressed ncurotropic ¢ff~t. Affecting the pain sensitivity nanogram amounts of MP evoke hyperaigesic response and increase the production of antibodies to SRBC 3-9 times. Milligram amoums of MP induce the hypoalgesic effect and do not affect antibody response. By sequeniial hydrophobic chromatography on Huorosorb and reversed phase HPLC highly purified peptide fractions with immunoregulatory, differentiation and neurotropic activities were isolated from the supematant of porcine bone marrow cell cultures. Several individual substances with immunostimulating as well as hypoand hyperalgesic effects were isolated. The amino acid composition of the isolated compounds was determined. Amino acid sequences of two peptides affecting pain sensitivity were deciphered. The relationship between neuroand immunotropic activities of MP are discussexl.