Involvement of PGE₂and RANTES inStaphylococcus aureus-induced fever in rats

Abstract

This study investigated the involvement of prostaglandins and regulated on activation, normal T cell expressed and secreted (RANTES), in fever induced by live Staphylococcus aureus (no. 25923, American Type Culture Collection) injection in rats. S. aureus was injected intraperitoneally at 10(9), 10(10), and 2 × 10(10) colony-forming units (CFU)/cavity, and body temperature (T(b)) was measured by radiotelemetry. The lowest dose of S. aureus induced a modest transient increase in T(b), whereas the two higher doses promoted similar long-lasting and sustained T(b) increases. Thus, the 10(10) CFU/cavity dose was chosen for the remaining experiments. The T(b) increase induced by S. aureus was accompanied by significant decreases in tail skin temperature and increases in PGE(2) levels in the cerebrospinal fluid (CSF) and hypothalamus but not in the venous plasma. Celecoxib (selective cyclooxygenase-2 inhibitor, 2.5 mg/kg po) inhibited the fever and the increases in PGE(2) concentration in the CSF and hypothalamus induced by S. aureus. Dipyrone (120 mg/kg ip) reduced the fever from 2.5 to 4 h and the PGE(2) increase in the CSF but not in the hypothalamus. S. aureus increased RANTES in the peritoneal exudate but not in the CSF or hypothalamus. Met-RANTES (100 μg/kg iv), a chemokine (C-C motif) receptor (CCR)1/CCR5 antagonist, reduced the first 6 h of fever induced by S. aureus. This study suggests that peripheral (local) RANTES and central PGE(2) production are key events in the febrile response to live S. aureus injection. As dipyrone does not reduce PGE(2) synthesis in the hypothalamus, it is plausible that S. aureus induces fever, in part, via a dipyrone-sensitive PGE(2)-independent pathway.

Dipyrone metabolite 4‐MAA induces hypothermia and inhibits PGE2‐dependent and ‐independent fever while 4‐AA only blocks PGE2‐dependent fever

“…injection of live Staphylococcus aureus or i.c.v. injection of ET‐1 (Malvar et al ., ; Martins et al ., ). As it is widely accepted that PGE 2 generated in the POA/AH appears to be the key mediator of the fever induced by LPS (Engblom et al ., ; Oka et al ., ; Lazarus et al ., ; Roth et al ., ; for review see Morrison and Nakamura, ), these results are in agreement with previous findings from our group (Malvar et al ., ) that dipyrone possesses an additional antipyretic mechanism that does not rely on hypothalamic PGE 2 synthesis inhibition.…”

“…Moreover, it has been shown that dipyrone inhibits PGE 2 synthesis through COX inhibition by two of its metabolites, 4‐MAA and 4‐AA, indicating that they may be the active metabolites of dipyrone (Hinz et al ., ; Pierre et al ., ). However, several studies from our group indicate that the antipyretic mechanism of dipyrone does not only involve PGE 2 synthesis inhibition (Souza et al ., ; Pessini et al ., ; Malvar et al ., ; Martins et al ., ).…”

Efficacy of Yougui pill combined with Buzhong Yiqi decoction in alleviating the sexual dysfunction in female rats through modulation of the gut microbiota

“…A previous study on Staphylococcus indicated that Staphylococcus aureus induced an increase in the levels of prostaglandin E(2) [PGE92)] in the hypothalamus (Martins et al. 2012 ), and the hypothalamus and limbic systems were involved in sexual arousal (Harsh and Clayton 2018 ). Moreover, PGE(2) might be used as a novel strategy for the treatment of erectile dysfunction (El Melegy et al.…”

Central mediators involved in the febrile response: effects of antipyretic drugs

“…The importance of these pathways may differ under different conditions, such as in fever that is observed after an injection of live E. coli . 208 or S. aureus 73 or fever of viral origin. 72 Additionally, the ability to generate PGs in the central nervous system is not sufficient to imply the involvement of these mediators in fever.…”

“…These eicosanoids have also been shown to be involved in the febrile response that is induced by other exogenous stimuli, such as Poly I:C, 72 Staphylococcus aureus, 73 and complex infectious conditions such as sepsis induced by cecal ligation and puncture. 75 The participation of these eicosanoids has also been suggested after stimulation with the TLR7 agonist imiquimod and TLR9 agonist ODN1668, which increased the expression of enzymes that are involved in PGE 2 synthesis in the rat hypothalamus.…”