Role of endogenous macrophage inflammatory protein‐2 in regulating fever induced by bacterial endotoxin in normal and immunosuppressed rats

Abstract

During myelosuppressive chemotherapy, Gram-negative bacterial infection with consequent exposure to lipopolysaccharide (LPS) is one of the most important causes of persistent fever. The classical model of the pathogenesis of fever suggests that pro-inflammatory cytokines, produced by leucocytes in the bloodstream in response to exogenous pyrogens such as bacterial LPS, represent the distal mediators of the febrile response. Neutrophils are the first effectors cells and the most prominent leucocyte population involved in acute bacterial infection. Macrophage inflammatory protein (MIP)-2 plays a crucial role in influencing early cell trafficking and neutrophil activation during pathophysiological processes and serves the same chemotactic function as human interleukin-8. In the present study, we investigated the role of MIP-2 in the development of a febrile response induced by LPS in immunocompetent and leukopenic rats. Intraperitoneal injection of LPS in leukopenic rats elicited a biphasic febrile response of rapid onset, the magnitude and duration of which were significantly greater than in immunocompetent animals. The febrile responses to LPS were accompanied by a pronounced induction of serum MIP-2 levels at 1, 2 and 4 h compared with their respective controls. In both normal and leukopenic rats, neutralization of endogenous MIP-2 bioactivity by systemic administration of antirat MIP-2 antibody caused a significant attenuation of the early phase of LPS fever. However, in contrast with normal rats, the second phase of fever was unimpaired by anti-MIP-2 in leukopenic rats. These findings suggest that circulating MIP-2 is involved in the generation of the early phase of LPS fever that contributes to the maintenance of the later phase of fever in immunocompetent, but not leukopenic, rats. Our data support a regulatory role for endogenous MIP-2 in initiating the fever responses to LPS. Furthermore, these results provide evidence that different cellular and humoral mechanisms are implicated in the development of a febrile response triggered by Gram-negative bacterial infections in leukopenic hosts.

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

“…That is, the reduction of circulating leukocytes by cyclophosphamide caused significantly enhanced fevers (in both magnitude and duration), and this effect was associated with a significant reduction of circulating inflammatory cytokines compared to those in immunocompetent animals. The present findings confirm previous experimental and clinical studies that show that the production of fever was not dependent on the presence of leukocytes in the peripheral circulation (3,24,28). Furthermore, they suggest that other, yet-to-be identified mediators as possible mechanisms of immune signaling are involved in the development of the acute-phase response to gram-negative and gram-positive infections.…”

“…These results are consistent with the idea that even when cytokines are detected in the blood, their timing does not always correlate with acute-phase activation after administration of immune stimuli (19). Concerning the role of administration of cyclophosphamide, it has previously been shown that this immunosuppressive drug induces a nonspecific leukopenia (fewer than 100 cells/ml for 6 to 7 days) (24,26) and a selective depletion of the lymphoid tissue (2,42). When such treated patients become afflicted with a bacterial infection, they develop high fevers.…”

“…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.…”

“…Chemotherapy-induced profound leukopenia in rats was achieved as described previously (24,26). In brief, rats were rendered leukopenic by i.p.…”

“…Circulating proinflammatory mediators such as interleukin-6 (IL-6), IL-8, macrophage inflammatory protein-2 (MIP-2), Creactive protein (CRP), and, more recently, procalcitonin (PCT) have been suggested to be predictive for a systemic microbial bloodstream infection in neutropenic hosts (4,8,11,12,24,35,36). However, the early cellular response to gramnegative and gram-positive bacteria is still unclear, and little is known about how the profile of these mediators during severe leukopenia might be affected by different microbial stimuli.…”