Macrophage Inflammatory Protein‐1β (MIP‐1β) Produced Endogenously in Brain During E. coli Fever in Rats

Abstract

Macrophage inflammatory protein-1 (MIP-1) evokes an intense fever, independent of a prostaglandin mechanism, and is now thought to play an important role in the defence response to bacterial pyrogens. The purpose of this study was 2-fold: (i) to determine whether the potent doublet of this cytokine, MIP-1beta, is actually produced in the brain in response to a pyrogenic dose of a lipopolysaccharide of Escherichia coli and (ii) to determine the anatomical site of synthesis of this cytokine in the brain. Following the intense fever produced by intraperitoneal administration of lipopolysaccharide in the unrestrained rat, MIP-1beta immunoreactivity was identified post mortem in two regions of the brain implicated in fever: the organum vasculosum laminae terminalis (OVLT) and the anterior hypothalamic, preoptic area (AH/POA). Microinjection of goat anti-mouse MIP-1beta antibody (anti-MIP-1beta) directly int the AH/POA markedly suppressed fever in rats in response to lipopolysaccharide. Further anti-MIP-1beta administered 180 min after the injection of lipopolysaccharide acted as an antipyretic and reversed the fever induced by the endotoxin. anti-MIP-1beta or control immunoglobulin G antibody microinjected into the hypothalamus immediately before the intraperitoneal injection of the control saline did not alter the temperature of the rats. Taken together, the present results demonstrate that MIP-1beta is produced in the brain in response to a bacterial endotoxin. These observations, in the light of earlier data on fever induced by MIP-1beta, further support the hypothesis that endogenously synthesized MIP-1beta acts as an intermediary factor in the evocation of fever by acting on the thermosensitive cells of the brain.

Circulating Inflammatory Mediators during Start of Fever in Differential Diagnosis of Gram-Negative and Gram-Positive Infections in Leukopenic Rats

“…A key event in the initiation of fever in response to acute bacterial infection is the induction and release of endogenous pyrogens (i.e., IL-1, IL-6, IL-8, RANTES, and MIPs) by polymorphonuclear and mononuclear leukocytes into the bloodstream (19,23,32,40,41,44). Normal leukocytes contain no detectable pyrogen and do not produce any during in vitro incubation.…”

“…Before the experiment, rats were weighed and arbitrarily assigned to body weight-matched experimental groups. Only animals whose body temperatures were stable and in the range of 36.9 to 37.3°C, which is within the range usually observed for rats under similar experimental conditions (23,24), and which were acclimated to experimental procedures were used to determine the effect of drug application. All treatments were carried out at the same time of day, with each rat being used only once for the experiment.…”

“…Fever was induced by i.p. administration of a single dose of LPS (100 g/kg) or MDP (100 g/kg), as previously described (23,30,33,41). Control animals received an equivalent volume of PFS as vehicle (1 ml/kg).…”

Macrophage Inflammatory Protein‐1β and Inducible Nitric Oxide Synthase Immunoreactivity in Rat Brain during Prostaglandin E2‐ or Lipopolysaccharide‐Induced Fevera

“…A prostaglandin (PGE) originally was proposed to be the intermediary messenger at the interface between the blood and brain and a febrile response 1 . However, much experimental evidence has failed to support the necessity of a PGE in the pathogenesis of fever 4–9 . In fact, a fever produced by a leucocyte pyrogen or pyrogenic cytokine such as IL‐8 or MIP‐1 is unaffected by a pharmacological inhibitor of PGE 2 activity 6,10–13 .…”

Intrahypothalamic Injection of the HIV-1 Envelope Glycoprotein Induces Fever via Interaction with the Chemokine System

“…Fever production is controlled by neuronal systems in the brain, particularly in the POAH (Boulant, 2000). It is believed to be caused by the synthesis and release from monocytes and macrophages of a number of well characterized endogenous pyrogenic factors, including interleukin-1, interleukin-6, tumor necrosis factor-␣, and macrophage inflammatory protein-1 (Myers et al, 1994;Miñ ano et al, 1996;Blatteis, 2006).…”