Soares Denis Melo, Figueiredo Maria José, Martins Juliano Manvailer, Machado Renes Resende, Kanashiro Alexandre, Malvar David do Carmo, Pessini Andréa Carla, Roth Joachim, Souza Glória Emília Petto
Laboratório de Farmacologia, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Av. do Café, s/n - Campus USP, 14040-903, Ribeirão Preto, SP, Brazil.
Brain Res. 2009 May 7;1269:54-60. doi: 10.1016/j.brainres.2009.03.003. Epub 2009 Mar 12.
The fever induced by lipopolysaccharide (LPS) depends on both prostaglandin-dependent and -independent pathways. One of the prostaglandin-independent pathways is sequentially orchestrated by pre-formed pyrogenic factor derived from LPS-stimulated macrophages (PFPF), corticotrophin releasing factor (CRF), endothelin-1 (ET-1) and interleukin-1 (IL-1). As macrophage-inflammatory-protein (MIP)-1 alpha (synonym CCL3) also induces a prostaglandin independent fever, the aim of the present study was to investigate a possible participation of CCL3/MIP-1 alpha within the prostaglandin-independent pathway of LPS-induced fever which depends on PFPF, CRF and ET-1. Therefore, rats received intracerebroventricular (i.c.v.) pre-treatment with anti-CCL3 monoclonal antibody (1 and 5 ng) at 1 h and 15 min before injection of LPS (lipopolysaccharide from E. coli; 5, 50 or 100 microg kg(-1), i.v.) or CCL3/MIP-1 alpha (500 pg, i.c.v.). Both doses of anti-CCL3 did not change the basal temperature but abolished the fever induced by CCL3/MIP-1 alpha. When given at the higher dose, anti-CCL3 did not influence the fever induced by i.v. injection of different doses of LPS, or i.c.v. administration of PFPF (200 ng), CRF (3 microg) or ET-1 (1 pmol). Bosentan, a non-selective ET(A/B) receptors antagonist (10 microg kg(-1), i.v.), reduced the fever induced by LPS but not that induced by CCL3/MIP-1 alpha. In contrast, alpha-helical CRF(9-41) (a non-selective CRF R1/R2 receptor antagonist; 25 microg injected i.c.v.) reduced CCL3/MIP-1 alpha-induced fever. In conclusion, the present results indicate that: i) CCL3/MIP-1 alpha is not an endogenous mediator of LPS-induced fever; ii) it is even not involved in the prostaglandin-independent pathway of the LPS-fever cascade and iii) its pyrogenic activity depends on synthesis/release of CRF.
脂多糖（LPS）诱导的发热取决于前列腺素依赖性和非依赖性途径。前列腺素非依赖性途径之一是由源自LPS刺激的巨噬细胞的预先形成的致热因子（PFPF）、促肾上腺皮质激素释放因子（CRF）、内皮素-1（ET-1）和白细胞介素-1（IL-1）依次协调。由于巨噬细胞炎性蛋白（MIP）-1α（同义词CCL3）也诱导前列腺素非依赖性发热，本研究的目的是调查CCL3/MIP-1α在LPS诱导的发热的前列腺素非依赖性途径中是否可能参与，该途径依赖于PFPF、CRF和ET-1。因此，在注射LPS（来自大肠杆菌的脂多糖；5、50或100μg kg(-1)，静脉注射）或CCL3/MIP-1α（500 pg，脑室内注射）前1小时和15分钟，给大鼠进行脑室内（i.c.v.）抗CCL3单克隆抗体（1和5 ng）预处理。两种剂量的抗CCL3均未改变基础体温，但消除了CCL3/MIP-1α诱导的发热。当给予较高剂量时，抗CCL3不影响静脉注射不同剂量LPS或脑室内注射PFPF（200 ng）、CRF（3μg）或ET-1（1 pmol）诱导的发热。波生坦，一种非选择性ET(A/B)受体拮抗剂（10μg kg(-1)，静脉注射），可降低LPS诱导的发热，但不能降低CCL3/MIP-1α诱导的发热。相反，α-螺旋CRF(9-41)（一种非选择性CRF R1/R2受体拮抗剂；25μg脑室内注射）可降低CCL3/MIP-1α诱导的发热。总之，目前的结果表明：i）CCL3/MIP-1α不是LPS诱导发热的内源性介质；ii）它甚至不参与LPS发热级联反应的前列腺素非依赖性途径；iii）其致热活性取决于CRF的合成/释放。
