ABSTRACT
Macrophage inflammatory protein (MIP)-1beta and RANTES (regulated on activation, normal T-cells expressed and secreted) are members of the CC-family of chemokines. Although these two peptides are structurally and functionally related to one another, each exhibits distinct features, which allows it to independently regulate specific aspects of the host inflammatory response. They evoked intense and functionally different febrile responses when applied directly on pyrogen-sensitive cells located in the in the preoptic area of the anterior hypothalamus (POA). The present experiments were carried out to test the central role of CCR5, a functional receptor for MIP-1beta and RANTES, in the febrile responses induced by these chemokines when injected directly into the POA. The microinjection of an equimolecular dose (50 pg) of either MIP-1beta or RANTES into the POA induced a rapid onset; monophasic fever in rats that persisted for a long period. The microinjection of 2.0 microg specific neutralizing antibodies against CCR5 (anti-CCR5) into the POA fails to affect the effects on body temperature induced by MIP-1beta. However, pretreatment with the same dose of anti-CCR5 suppressed the febrile response induced by RANTES given at the same site. The microinjection of control IgG or anti-CCR5 does not affect basal temperature, when administered alone at the same hypothalamic site. The present experiments show that hypothalamic CCR5 are functionally involved in the febrile response induced by RANTES, but not by MIP-1beta. They also suggest the existence of functionally different components in the presumptive primary locus of the thermoregulatory controller, in which both chemotactic cytokines, together other mediators, could play a relevant role in the complex process of fever pathogenesis.
Subject(s)
Chemokines, CC/adverse effects , Fever/chemically induced , Pyrogens/adverse effects , Receptors, CCR5/administration & dosage , Animals , Antibodies/administration & dosage , Antibodies/physiology , Body Temperature/drug effects , Body Temperature/immunology , CCR5 Receptor Antagonists , Cerebrospinal Fluid/chemistry , Cerebrospinal Fluid/immunology , Chemokine CCL4 , Chemokine CCL5/administration & dosage , Chemokine CCL5/antagonists & inhibitors , Chemokine CCL5/immunology , Chemokines, CC/administration & dosage , Chemokines, CC/immunology , Fever/immunology , Fever/physiopathology , Fever/prevention & control , Heating , Immunoglobulin G/administration & dosage , Immunoglobulin G/immunology , Immunoglobulin G/pharmacology , Macrophage Inflammatory Proteins/adverse effects , Macrophage Inflammatory Proteins/antagonists & inhibitors , Macrophage Inflammatory Proteins/immunology , Male , Microinjections/methods , Preoptic Area/anatomy & histology , Preoptic Area/drug effects , Preoptic Area/physiopathology , Pyrogens/administration & dosage , Pyrogens/immunology , Rats , Rats, Wistar , Receptors, CCR5/immunology , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Recombinant Proteins/metabolism , Stereotaxic Techniques , Time FactorsABSTRACT
BACKGROUND: Eotaxin and MCP-3 (CC chemokines), owing to their preferential action on eosinophils, seem to be the very importance in the patophysiology of allergic rhinitis and asthma. The purpose of this study was to examine the effect of intranasally administered eotaxin and MCP-3 after specific allergen priming on the influx of inflammatory cells and their soluble mediators into the nasal mucosa. METHODS: Eotaxin and MCP-3 have been applied intranasally at the increasing doses of 1, 5 and 10 microg to allergic patients after allergen priming. The 'nasal pool' technique was used. The cell count and biochemical parameters in nasal lavage were evaluated before 30 min, and 4 and 24 h after the challenge with chemokines. RESULTS: Both eotaxin and MCP-3 induced the increase in clinical 'score' lasting till 24 h. Eosinophil influx into nasal mucosa after provocation with eotaxin was also observed. The challenge with MCP-3 did not induce any significant changes in nasal lavage fluid. CONCLUSIONS: Eotaxin is likely to play an important role in the pathogenesis of allergic conditions in humans. MCP-3 did not induce inflammatory cell influx into nasal mucosa. The role of this chemokine in the pathogenesis of allergic inflammation is difficult to assess and requires further studies.
