RESUMO
IL-13 is a cytokine known to play a role in several pulmonary diseases, including asthma and fibrosis. The role of IL-13 in the context of pulmonary changes induced by helminth infection is unclear. Rats experimentally infected with Strongyloides venezuelensis and treated with anti-IL-13 neutralizing antibody were used to evaluate the role of IL-13 on functional and inflammatory changes of host lungs, and on parasite control. S. venezuelensis-induced airway hyperreactivity was IL-13-independent, but IL-13 played an essential role in driving airway mucus production and eosinophil infiltration. IL-13 was important for the control of egg production but not establishment in the intestine.
Assuntos
Interleucina-13/imunologia , Strongyloides/imunologia , Strongyloides/patogenicidade , Estrongiloidíase/imunologia , Estrongiloidíase/patologia , Animais , Eosinófilos/imunologia , Interleucina-13/antagonistas & inibidores , Pulmão/parasitologia , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Muco/metabolismo , Ratos , Ratos Wistar , Testes de Função Respiratória , Estrongiloidíase/microbiologiaRESUMO
In the present study, we used the electronic version of the von Frey test to investigate the role of cytokines (TNF-alpha and IL-1beta) and chemokines (KC/CXCL-1) in the genesis of mechanical hypernociception during antigen-induced inflammation in mice. The nociceptive test consisted of evoking a hindpaw flexion reflex with a hand-held force transducer (electronic anesthesiometer) adapted with a 0.5 mm(2) polypropylene tip. The intraplantar administration of methylated bovine serum albumin (mBSA) in previously immunized (IM), but not in sham-immunized (SI) mice, induced mechanical hypernociception in a dose-dependent manner. Hypernociception induced by antigen was reduced in animals pretreated with IL-1ra and reparixin (a non-competitive allosteric inhibitor of CXCR2), and in TNF receptor type 1 deficient (TNFR1-/-) mice. Consistently, antigen challenge induced a time-dependent release of TNF-alpha, IL-1beta and KC/CXCL-1 in IM, but not in SI, mice. The increase in TNF-alpha levels preceded the increase in IL-1beta and KC/CXCL1. Antigen-induced release of IL-1beta and KC/CXCL1 was reduced in TNFR1-/- mice, and TNF-alpha-induced hypernociception was inhibited by IL-1ra and reparixin. Hypernociception induced by IL-1beta in immunized mice was inhibited by indomethacin, whereas KC/CXCL1-induced hypernociception was inhibited by indomethacin and guanethidine. Antigen-induced hypernociception was reduced by indomethacin and guanethidine and abolished by the two drugs combined. Together, these results suggest that inflammation associated with an adaptive immune response induces hypernociception that is mediated by an initial release of TNF-alpha, which triggers the subsequent release of IL-1beta and KC/CXCL1. The latter cytokines in turn stimulate the release of the direct-acting final mediators, prostanoids and sympathetic amines.
Assuntos
Quimiocinas/metabolismo , Citocinas/metabolismo , Hiperalgesia/imunologia , Hipersensibilidade Tardia/imunologia , Neuroimunomodulação/imunologia , Nociceptores/imunologia , Animais , Quimiocina CXCL1/imunologia , Modelos Animais de Doenças , Feminino , Hiperalgesia/genética , Hiperalgesia/fisiopatologia , Hipersensibilidade Tardia/genética , Hipersensibilidade Tardia/fisiopatologia , Mediadores da Inflamação/farmacologia , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuroimunomodulação/genética , Medição da Dor , Limiar da Dor , Estimulação Física , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
Neutrophil migration is responsible for tissue damage observed in inflammatory diseases. Neutrophils are also implicated in inflammatory nociception, but mechanisms of their participation have not been elucidated. In the present study, we addressed these mechanisms in the carrageenan-induced mechanical hypernociception, which was determined using a modification of the Randall-Sellito test in rats. Neutrophil accumulation into the plantar tissue was determined by the contents of myeloperoxidase activity, whereas cytokines and PGE(2) levels were measured by ELISA and radioimmunoassay, respectively. The pretreatment of rats with fucoidin (a leukocyte adhesion inhibitor) inhibited carrageenan-induced hypernociception in a dose- and time-dependent manner. Inhibition of hypernociception by fucoidin was associated with prevention of neutrophil recruitment, as it did not inhibit the hypernociception induced by the direct-acting hypernociceptive mediators, PGE(2) and dopamine, which cause hypernociception, independent of neutrophils. Fucoidin had no effect on carrageenan-induced TNF-alpha, IL-1beta, and cytokine-induced neutrophil chemoattractant 1 (CINC-1)/CXCL1 production, suggesting that neutrophils were not the source of hypernociceptive cytokines. Conversely, hypernociception and neutrophil migration induced by TNF-alpha, IL-1beta, and CINC-1/CXCL1 was inhibited by fucoidin, suggesting that neutrophils are involved in the production of direct-acting hypernociceptive mediators. Indeed, neutrophils stimulated in vitro with IL-1beta produced PGE(2), and IL-1beta-induced PGE(2) production in the rat paw was inhibited by the pretreatment with fucoidin. In conclusion, during the inflammatory process, the migrating neutrophils participate in the cascade of events leading to mechanical hypernociception, at least by mediating the release of direct-acting hypernociceptive mediators, such as PGE(2). Therefore, the blockade of neutrophil migration could be a target to development of new analgesic drugs.
Assuntos
Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Neutrófilos/fisiologia , Dor/fisiopatologia , Animais , Carragenina/farmacologia , Técnicas de Cultura de Células , Quimiocina CXCL1/sangue , Citocinas/sangue , Dinoprostona/metabolismo , Membro Posterior/irrigação sanguínea , Hiperalgesia/sangue , Inflamação/sangue , Interleucina-1/sangue , Masculino , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Dor/sangue , Limiar da Dor , Polissacarídeos/farmacologia , Ratos , Ratos Wistar , Tempo de Reação , Fenômenos Fisiológicos da Pele , Fator de Necrose Tumoral alfa/sangueRESUMO
The authors describe the evidences supporting the role of cytokines in experimental pain, discussing possible approaches for pain control using cytokine-targeting therapies.
Os autores fazem uma revisão sobre evidências que demonstram o papel de citocinas em modelos experimentais de dor, discutindo possíveis terapias com alvo em citocinas para controle da dor.
Assuntos
Humanos , Analgesia , Citocinas , Hiperalgesia , Dor , Medição da DorRESUMO
Kinin receptors are involved in the genesis of inflammatory pain. However, there is controversy concerning the mechanism by which B(1) and B(2) kinin receptors mediate inflammatory hypernociception. In the present study, the role of these receptors on inflammatory hypernociception in mice was addressed. Mechanical hypernociception was detected with an electronic pressure meter paw test in mice and cytokines were measured by ELISA. It was observed that in naïve mice a B(2) (d-Arg-Hyp(3), d-Phe(7)-bradykinin) but not a B(1) kinin receptor antagonist (des-Arg(9)-[Leu(8)]-bradykinin, DALBK) inhibited bradykinin- and carrageenin-induced hypernociception. Bradykinin-induced hypernociception was inhibited by indomethacin (5 mg/kg) and guanethidine (30 mg/kg), while not affected by IL-1ra (10 mg/kg) or antibody against keratinocyte-derived chemokine (KC/CXCL-1, 500 ng/paw) or in TNFR1 knockout mice. By contrast, in previously lipopolysaccharide (LPS)-primed mouse paw, B(1) but not B(2) kinin receptor antagonist inhibited bradykinin hypernociception. Furthermore, B(1) kinin receptor agonist induced mechanical hypernociception in LPS-primed mice, which was inhibited by indomethacin, guanethidine, antiserum against TNF-alpha or IL-1ra. This was corroborated by the induction of TNF-alpha and IL-1beta release by B(1) kinin receptor agonist in LPS-primed mouse paws. Moreover, B(1) but not B(2) kinin receptor antagonist inhibited carrageenin-induced hypernociception, and TNF-alpha and IL-1beta release as well, in LPS-primed mice. These results suggest that in naïve mice the B(2) kinin receptor mediates inflammatory hypernociception dependent on prostanoids and sympathetic amines, through a cytokine-independent mechanism. On the other hand, in LPS-primed mice, the B(1) kinin receptor mediates hypernociception by a mechanism dependent on TNF-alpha and IL-1beta, which could stimulate prostanoid and sympathetic amine production.
Assuntos
Hiperalgesia/fisiopatologia , Inflamação/fisiopatologia , Interleucina-1beta/fisiologia , Receptores da Bradicinina/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Anticorpos/farmacologia , Bradicinina/administração & dosagem , Bradicinina/análogos & derivados , Bradicinina/farmacologia , Antagonistas de Receptor B1 da Bradicinina , Antagonistas de Receptor B2 da Bradicinina , Antagonistas dos Receptores da Bradicinina , Carragenina/administração & dosagem , Carragenina/toxicidade , Relação Dose-Resposta a Droga , Guanetidina/farmacologia , Hiperalgesia/induzido quimicamente , Hiperalgesia/prevenção & controle , Indometacina/farmacologia , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prostaglandinas/fisiologia , Receptor B1 da Bradicinina/agonistas , Receptor B1 da Bradicinina/fisiologia , Receptor B2 da Bradicinina/fisiologia , Receptores da Bradicinina/agonistas , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Receptores Tipo I de Fatores de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
There is pre-clinical evidence that therapies targeting IL-18 might be beneficial in controlling arthropathies, which are accompanied by hypernociception (nociceptor sensitization). In the present study, we addressed the hypernociceptive role of IL-18 in a model of antigen-induced inflammation in mice and its mechanisms. In naïve mice, the intraplantar injection of IL-18 induced dose- and time-dependent mechanical hypernociception, which was inhibited in IFN-gamma deficient (-/-) mice, and by the pre-treatment with bosentan (dual endothelin [ET] receptor antagonist), BQ123 (ET(A) receptor antagonist) or indomethacin (cyclooxygenase inhibitor). IL-18 hypernociception was unaffected in TNFR1(-/-) mice or by the pre-treatment with sIL-15Ralpha (soluble form of IL-15 receptor), BQ788 (ET(B) receptor antagonist) or guanethidine (sympathetic blocker). The ovalbumin (OVA) challenge-induced mechanical hypernociception in immunized mice was inhibited by the pre-treatment with anti-IL-18 antibody or in IL-18(-/-) mice. Furthermore, IL-18 induced significant IFN-gamma production in the paw skin of naïve mice. The OVA challenge-induced IFN-gamma and ET-1 productions were inhibited in IL-18(-/-) immunized mice, as well as ET-1 production in IFN-gamma(-/-) immunized mice. In addition, significant PGE2 production was detected after IL-18 or ET-1 (via ET(A) receptors) injection in naïve mice. Taken together with previous data, these results suggest that IL-18 plays a significant role in antigen-induced inflammatory hypernociception via the production of IFN-gamma, ET-1 and PGE2. Thus, IL-18 and IL-18-downstream mediators demonstrated herein might constitute targets to inhibit antigen-induced inflammatory pain.
Assuntos
Interferon gama/imunologia , Interleucina-18/imunologia , Limiar da Dor/fisiologia , Dor/imunologia , Receptores Tipo I de Fatores de Necrose Tumoral/imunologia , Transdução de Sinais/imunologia , Animais , Antígenos/imunologia , Dinoprostona/metabolismo , Relação Dose-Resposta a Droga , Interferon gama/genética , Interleucina-18/administração & dosagem , Interleucina-18/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ovalbumina/imunologia , Prostaglandina-Endoperóxido Sintases/imunologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Receptor de Endotelina A/metabolismo , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Estresse Mecânico , Fatores de TempoRESUMO
Pain is one of the classical signs of the inflammatory process in which sensitization of the nociceptors is the common denominator. This sensitization causes hyperalgesia or allodynia in humans, phenomena that involve pain perception (emotional component+nociceptive sensation). As this review focuses mainly on animal models, which don't allow discrimination of the emotional component, the terms nociception and hypernociception are used to describe overt behavior induced by mechanical stimulation and increase of nociceptor sensitivity, respectively. Pro- and anti-inflammatory cytokines and chemokines are endogenous small protein mediators released by local or migrating cells whose balance modulates the intensity of inflammatory response. The inflammatory stimuli or tissue injuries stimulate the release of characteristic cytokine cascades, which ultimately trigger the release of final mediators responsible for inflammatory pain. These final mediators, such as prostanoids or sympathetic amines, act directly on the nociceptors to cause hypernociception, which results from the lowering of threshold due to modulation of specific voltage-dependent sodium channels. Furthermore, a direct effect of cytokines on nociceptors is also described. On the other hand, there are also anti-inflammatory cytokines, such as interleukin (IL)-10, IL-4 and IL-13, and IL-1 receptor antagonists (IL-1ra), which inhibit the production of hypernociceptive cytokines and/or the final hypernociceptive mediators, preventing the installation of or the increase in the hypernociception. This review highlights the importance of the direct and indirect actions of cytokines and chemokines in inflammatory and neuropathic hypernociception, emphasizing the evidence suggesting these molecules are potential targets to develop novel drugs and therapies for the treatment of pain.
Assuntos
Quimiocinas/imunologia , Citocinas/imunologia , Dor/tratamento farmacológico , Analgésicos/farmacologia , Animais , Humanos , Dor/imunologiaRESUMO
The anti-nociceptive effect of thalidomide on zymosan-induced articular knee joint incapacitation in rats was investigated. Thalidomide (5-45 mg/kg), given 30 min before but not 2 h after the intra-articular injection of zymosan, inhibited the nociceptive response in a dose-dependent manner. Furthermore, thalidomide pretreatment significantly reduced the concentration of tumor necrosis factor-alpha (TNF-alpha, -68.4%) in the exudate of zymosan-injected joints, but not those of interleukin-1beta, interleukin-6, CINC-1 or interleukin-10. The expression of TNF-alpha, determined by immunohistochemical staining, in synovial tissues obtained from articular joints injected with zymosan was also inhibited by thalidomide pretreatment. The anti-nociceptive effect of thalidomide was not reversed by the co-administration of an opioid receptor antagonist, naloxone, suggesting that endogenous opioids do not mediate the anti-nociceptive effect of thalidomide in this model. In conclusion, the anti-nociceptive activity of thalidomide in zymosan-induced articular incapacitation is associated with the inhibition of TNF-alpha by resident synovial cells.
Assuntos
Analgésicos/farmacologia , Artralgia/prevenção & controle , Artrite Experimental/prevenção & controle , Articulação do Joelho/efeitos dos fármacos , Talidomida/farmacologia , Analgésicos/administração & dosagem , Animais , Artrite Experimental/induzido quimicamente , Artrite Experimental/fisiopatologia , Quimiocina CXCL1 , Quimiocinas CXC/biossíntese , Exsudatos e Transudatos/efeitos dos fármacos , Exsudatos e Transudatos/metabolismo , Imuno-Histoquímica , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Injeções Intraperitoneais , Interleucina-1/biossíntese , Interleucina-6/biossíntese , Articulação do Joelho/metabolismo , Articulação do Joelho/fisiopatologia , Masculino , Naloxona/administração & dosagem , Naloxona/farmacologia , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/farmacologia , Ratos , Ratos Wistar , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Talidomida/administração & dosagem , Fator de Necrose Tumoral alfa/biossíntese , ZimosanRESUMO
Interleukin-12 (IL-12) is an inflammatory Th1-driving cytokine that has been clinically used as immune therapy and vaccine adjuvant. Recently, it was reported that patients receiving IL-12 presented hyperalgesia. In the present study, we investigated the mechanical hyperalgesic effect of IL-12 in rats using two tests: 1) paw constant pressure and 2) electronic pressure-meter. In both tests, intraplantar administration of IL-12 (3-30 ng paw(-1)) caused a dose- and time-dependent mechanical hyperalgesia, which peaked between 3 to 5 h, remaining significantly different from control levels until 7 h and resolved 24 h postinjection. However, the same doses of IL-12 did not induce thermal hyperalgesia, determined using the Hargreaves test. Pretreatments with effective doses of indomethacin (2.5 mg kg(-1)), atenolol (1 mg kg(-1)), 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-t-butylthioindol-2-yl]-2,2-dimethylpropanoic acid, sodium (MK886) (5-lipoxygenase activating protein inhibitor; 1 mg kg(-1)), or cyclo[(D)Trp-(D)Asp-Pro-(D)Val-Leu] (BQ123) [endothelin (ET)(A) receptor antagonist; 30 nmol paw(-1)] did not inhibit IL-12-evoked mechanical hyperalgesia (10 ng paw(-1)). However, dexamethasone (2 mg kg(-1)), morphine (3-12 microg paw(-1)), and N-cys-2,6 dimethylpiperidinocarbonyl-L-gamma-methylleucyl-D-1-methoxycarboyl-d-norleucine (BQ788) (ET(B) receptor antagonist; 3-30 nmol paw(-1)) did inhibit IL-12 hyperalgesia. Furthermore, neither pretreatment with effective doses of antiserum against rat-TNF-alpha (50 microl paw(-1)) nor against IL-18 (10 microg paw(-1)) inhibited the IL-12-induced hyperalgesia. Likewise, antiserum against IL-12 (10 ng paw(-1)) did not alter IL-18-induced hyperalgesia. In conclusion, we demonstrated for the first time that IL-12 is a prohyperalgesic cytokine that induces mechanical hyperalgesia mediated by endothelin action on the ET(B) receptor. Therefore, endothelin receptor antagonism could be beneficial in controlling IL-12 therapy-induced pain or hyperalgesia.
Assuntos
Analgésicos , Endotelinas , Interleucina-12/farmacologia , Dor/induzido quimicamente , Dor/prevenção & controle , Receptor de Endotelina B/efeitos dos fármacos , Analgésicos Opioides/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anticorpos Bloqueadores/farmacologia , Citocinas/fisiologia , Relação Dose-Resposta a Droga , Eicosanoides/farmacologia , Antagonistas do Receptor de Endotelina A , Pé , Temperatura Alta , Hiperalgesia/induzido quimicamente , Hiperalgesia/psicologia , Injeções Subcutâneas , Interleucina-12/administração & dosagem , Interleucina-12/antagonistas & inibidores , Masculino , Morfina/farmacologia , Medição da Dor/efeitos dos fármacos , Estimulação Física , Ratos , Ratos Wistar , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
The antihyperalgesic effect of pentoxifylline was investigated in three experimental pain models. Pentoxifylline (0.5-1.6 mg kg(-1)) given 30 min before the stimulus significantly inhibited the writhing response induced by the intraperitoneal (i.p.) administration of either acetic acid (-90%) or zymosan (-83%), but not that of iloprost, in mice, as well as the zymosan-induced articular hyperalgesia in the zymosan arthritis in rats (-50%). Pentoxifylline also inhibited the mechanical hypernociception in rats induced by the intraplantar injection of either carrageenin (-81%), bradykinin (-56%) or tumor necrosis factor alpha (TNF-alpha; -46%), but not that induced by interleukin-1beta (IL-1beta) or prostaglandin E(2) (PGE(2)). Pentoxifylline did not inhibit the nociceptive response in the hot plate test in mice. Further, the antinociceptive effect of pentoxifylline in the writhing test in mice and the zymosan-induced articular hyperalgesia were not reversed by the coadministration of the opioid receptor antagonist naloxone. Thus, pentoxifylline antinociceptive effect is probably not mediated at a central level. Pentoxifylline significantly reduced TNF-alpha (-43%) and IL-1beta (-42%) concentrations in the joint exudates of rats stimulated by intra-articular injection of zymosan and the production of both cytokines (-66 and -86%, respectively) by mouse peritoneal macrophages stimulated in vivo with zymosan as well as the expression of TNF-alpha at the tissue level in carrageenin-injected rat paws. In conclusion, the antinociceptive activity of pentoxifylline is associated with the inhibition of the release of both TNF-alpha and IL-1beta.