Tumor necrosis factor, interleukin‐1 and interleukin‐8 mediate the nociceptive activity of the supernatant of LPS‐stimulated macrophages

Abstract

It has been suggested that the supernatant of LPSstimulated macrophages (macrophage nociceptive factor, MNF) promotes nociception in mice. Intraperitoneal administration of MNF induced dose-related writhing, which reached a plateau between 18 and 26 min after injection and decreased within 60 min. The release of MNF was inhibited by the pretreatment of the macrophages with cycloheximide, a protein synthesis inhibitor, or with the glucocorticoid dexamethasone. Cyclooxygenase inhibitors, such as indomethacin or paracetamol, had no effect. The MNF-induced nociception was inhibited in a dose-related manner by pretreatment of the animals with indomethacin, paracetamol or dexamethasone. Pretreatment of the animals with the sympatholytics guanethidine and atenolol partially reduced the MNF nociception, which was abolished by the combination of guanethidine or atenolol with indomethacin. The preincubation of MNF with antisera against TNF-α, IL-1 or IL-8 partially inhibited its nociceptive effect. Intraperitoneal injection of a mixture of the recombinants cytokines TNF-α, IL-1 and IL-8 mimicked MNF nociception. The individual injection of these cytokines was unable to induce the nociceptive effect. In conclusion, our data suggest that the nociceptive activity of the supernatant of LPSstimulated macrophages is explained by the presence of TNF-α, IL-1 and IL-8, the nociceptive activity of which (in mice) seems to be due to the release of cyclooxygenase and sympathetic metabolites.

Periprosthetic UHMWPE Wear Debris Induces Inflammation, Vascularization, and Innervation After Total Disc Replacement in the Lumbar Spine

“…It is well accepted from studies on painful DDD that the pathology involves the proliferation of fibroblasts and infiltration of macrophages into the annulus fibrosus in conjunction with the production of pain-associated proteins [4,8,43]. Specifically, activated macrophages have been reported to contribute to experimental pain states by releasing factors such as TNFa, IL-1b, IL-8, NGF, nitric oxide, and prostanoids [22,33,37]. In the context of periprosthetic wear debris, joint arthroplasty studies revealed that UHMWPE particles can activate both fibroblasts and macrophages to secrete TNFa and IL-1ß, which can synergistically contribute to the recruitment of more macrophages [19,32].…”

“…Specifically, activated macrophages can contribute to experimental pain states by releasing proinflammatory cytokines such as tumor necrosis factor-a (TNFa) and interleukin (IL)-1b [22,33,37]; these are both increased in the nucleus pulposus and annulus fibrosus of painful degenerative discs [17,42]. It is important to note that TNFa and IL-1ß are not only potent stimulators of proinflammatory reactions, but both have the potential to induce neural ingrowth into the disc and mediate pain sensitization by upregulating the expression of factors such as nerve growth factor (NGF) and substance P [1].…”

Antinociceptive Effects of Interleukin-4, -10, and -13 on the Writhing Response in Mice and Zymosan-Induced Knee Joint Incapacitation in Rats

“…The mediators involved in the genesis of the nociception observed in the writhing test are the eicosanoids and sympathomimetic amines, the release of which is preceded by the release of the nociceptive cytokines TNF-␣, IL-1␤, and IL-8 (Duarte et al, 1988;Thomazzi et al, 1997;Ribeiro et al, 2000). The rat knee-joint incapacitation test was designed for the study of articular incapacitation, defined as the inability of a rat subjected to an experimentally induced arthritis to deambulate normally (Tonussi and Ferreira, 1992).…”

“…TNF-␣ induced the release of IL-1␤ and -6, which stimulated the production of cyclooxygenase products and IL-8, which, in turn, stimulated production of sympathomimetic mediators (Cunha et al, 1991(Cunha et al, , 1992aFerreira et al, 1993). In a different model, the writhing test in mice, zymosan, or acetic acid-induced writhing was also mediated by cyclooxygenase products and sympathomimetic amines, the release of which was mediated by TNF-␣, IL-1␤, and IL-8 (Duarte et al, 1988;Thomazzi et al, 1997). These cytokines appear to be released by resident peritoneal macrophages and mast cells since the depletion of these cells from the mouse peritoneal cavity abolished the acetic acid-or zymosan-induced writhing response.…”

Analgesic activity ofEugenia jambolanaleave constituent: A dikaempferol rhamnopyranoside from ethyl acetate soluble fraction

“…The writhing test can predict effective analgesic doses for agents that can be used in humans (Dubinsky et al, 1987;Eaton, 2003). The mediators involved in the genesis of the nociception observed in the writhing test are the eicosanoids and sympathomimetic amines, the release of which is preceded by the release of the nociceptive cytokines TNF-a, IL-1b, and IL-8 (Duarte et al, 1988;Ribeiro et al, 2000a;Thomazzi et al, 1997). The writhing response of the mouse to an injection of noxious chemical is not a very specific nociception model, it is important to reveal a general antinociceptive effect of the compound under study (Marchioro et al, 2005).…”