Role of interleukin-1 in fever and inflammation

• The proinflammatory cytokines interleukin (IL) -1α, IL-1β and IL-6 are key mediators in the host's response to injury and infection. One of the systemic responses elicited by these proinflammatory cytokines, when injected peripherally or centrally, is fever. Thus, these proteins may act as endogenous pyrogens.We have shown that for a functional IL-1 mediated febrile response in vivo, both IL-1 receptor type I (IL-1RI) and IL-1 receptor accessory protein (IL-1RAcP) are necessary components, as knockout (KO) mice, lacking either IL-1RI or IL-1RAcP proteins, do not mount febrile responses to rrIL-1 (25-50 μg/kg, i.p.) injections, whereas they responded with fever when challenged by LPS (50 μg/kg, i.p.). These results suggest that IL-1 induces fever via signalling through a receptor complex, consisting of both IL-1RI and IL-1RAcP. We have also shown that IL-1β cannot induce NFκB translocation to the nucleus in primary astrocyte cultures derived from IL-1RAcP KO mice, suggesting a signalling role for this protein in mouse astrocytes.When the regulation of interleukin-1β converting enzyme (ICE, caspase-1) was studied in rat after peripheral LPS treatment (2 mg/kg, i.p.), elevations were seen, on both mRNA levels and enzyme activity in the pituitary, whereas in adrenal glands, an increase of mRNA levels did not coincide with upregulated enzyme activity. However, LPS was further shown to differentially regulate ICE isoforms, some of which are supposed to act as endogenous inhibitors of ICE activity. Thus, ICE activity seems to be tightly controlled on a transcriptional level, where regulation of ICE isoforms play an important role, as well as at the post transcriptional level.We have also shown that treatment with a neurotoxic fragment of β-amyloid, βA(25-35), induces a reactive phenotype of rat primary astrocyte cultures. The progression of this reactive phenotype was shown to coincide with elevated mRNA levels of IL-1α and IL-6. In addition, βA(25-35) treatment of primary astrocyte cultures derived from IL-1RI KO mice, induced a hypersensitive IL-1α response and a decreased IL-6 response. IL-1a and IL-6 are therefore proposed to be important molecules for development of reactive gliosis, and we also propose that signalling via IL-1RI is necessary for a full-scale induction of IL-6 mRNA.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

Neurochemistry

Neurokemi

neurokemi och neurotoxikologi

Neurochemistry and Neurotoxicology

Publikations- och innehållstyp

vet (ämneskategori)

dok (ämneskategori)