Mechanisms underlying the hyperalgesic responses triggered by joint activation of TLR4.

Background: Toll-like receptors (TLRs) including TLR4 and their signal pathways contribute to the pathogenesis of arthritis. Herein, we evaluated the mechanisms underlying the hyperalgesic response caused by TLR4 activation in the tibio-tarsal joint in mice.

Methods: Joint inflammatory hyperalgesia was induced by intra-articular (ia) injection of LPS (lipopolysaccharide- TLR4 agonist) in C57BL/6, TLR4, TLR2, MyD88, TRIF, TNFR1/2 and IL-1R1 knockout () mice.

Lipopolysaccharide induces inflammatory hyperalgesia triggering a TLR4/MyD88-dependent cytokine cascade in the mice paw.

Inflammatory pain can be triggered by different stimuli, such as trauma, radiation, antigen and infection. In a model of inflammatory pain caused by infection, injection in the mice paw of lipopolysaccharide (LPS), a Toll-like receptor 4 (TLR4) agonist, produces mechanical hyperalgesia. We identify here the TLR4 linked signaling pathways that elicit this response.

The role of PAF/PAFR signaling in zymosan-induced articular inflammatory hyperalgesia.

Platelet-activating factor (PAF) and its receptor (PAFR) have been shown to be involved in several inflammatory events, including neutrophil chemoattraction and nociception. The present study addressed the role of PAF in the genesis of articular hyperalgesia in a model of joint inflammation. Zymosan-induced articular hyperalgesia, oedema and neutrophil migration were dose-dependently reduced following pretreatment with selective PAFR antagonists, UK74505 (5, 10 and 20 mg/kg) and PCA4248 (3, 10, 30 mg/kg).

Trypanosoma cruzi adjuvants potentiate T cell-mediated immunity induced by a NY-ESO-1 based antitumor vaccine.

Immunological adjuvants that induce T cell-mediate immunity (TCMI) with the least side effects are needed for the development of human vaccines. Glycoinositolphospholipids (GIPL) and CpGs oligodeoxynucleotides (CpG ODNs) derived from the protozoa parasite Trypanosoma cruzi induce potent pro-inflammatory reaction through activation of Toll-Like Receptor (TLR)4 and TLR9, respectively. Here, using mouse models, we tested the T.

Toll-like receptor 2/MyD88 signaling mediates zymosan-induced joint hypernociception in mice: participation of TNF-α, IL-1β and CXCL1/KC.

Arthritic pain is a serious health problem that affects a large number of patients. Toll-like receptors (TLRs) activation within the joints has been implicated in pathophysiology of arthritis. However, their role in the genesis of arthritic pain needs to be demonstrated.

Caspase-1 is involved in the genesis of inflammatory hypernociception by contributing to peripheral IL-1β maturation.

Background: Caspase-1 is a cysteine protease responsible for the processing and secretion of IL-1β and IL-18, which are closely related to the induction of inflammation. However, limited evidence addresses the participation of caspase-1 in inflammatory pain. Here, we investigated the role of caspase-1 in inflammatory hypernociception (a decrease in the nociceptive threshold) using caspase-1 deficient mice (casp1-/-).

IL-33 induces neutrophil migration in rheumatoid arthritis and is a target of anti-TNF therapy.

Objectives: Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis.

Methods And Results: Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression.

Targeting endothelin ETA and ETB receptors inhibits antigen-induced neutrophil migration and mechanical hypernociception in mice.

Endothelin may contribute to the development of inflammatory events such as leukocyte recruitment and nociception. Herein, we investigated whether endothelin-mediated mechanical hypernociception (decreased nociceptive threshold, evaluated by electronic pressure-meter) and neutrophil migration (myeloperoxidase activity) are inter-dependent in antigen challenge-induced Th1-driven hind-paw inflammation. In antigen challenge-induced inflammation, endothelin (ET) ET(A) and ET(B) receptor antagonism inhibited both hypernociception and neutrophil migration.

Dual role of hydrogen sulfide in mechanical inflammatory hypernociception.

Hydrogen sulfide (H(2)S) is an endogenous gas involved in several biological functions, including modulation of nociception. However, the mechanisms involved in such modulation are not fully elucidated. The present study demonstrated that the pretreatment of mice with PAG, a H(2)S synthesis inhibitor, reduced LPS-induced mechanical paw hypernociception.

Role of cytokines in mediating mechanical hypernociception in a model of delayed-type hypersensitivity in mice.

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.

IL-33 mediates antigen-induced cutaneous and articular hypernociception in mice.

IL-33, a new member of the IL-1 family, signals through its receptor ST2 and induces T helper 2 (Th2) cytokine synthesis and mediates inflammatory response. We have investigated the role of IL-33 in antigen-induced hypernociception. Recombinant IL-33 induced cutaneous and articular mechanical hypernociception in a time- and dose-dependent manner.

Involvement of LTB4 in zymosan-induced joint nociception in mice: participation of neutrophils and PGE2.

Leukotriene B4 (LTB4) mediates different inflammatory events such as neutrophil migration and pain. The present study addressed the mechanisms of LTB4-mediated joint inflammation-induced hypernociception. It was observed that zymosan-induced articular hypernociception and neutrophil migration were reduced dose-dependently by the pretreatment with MK886 (1-9 mg/kg; LT synthesis inhibitor) as well as in 5-lypoxygenase-deficient mice (5LO(-/-)) or by the selective antagonist of the LTB(4) receptor (CP105696; 3 mg/kg).

TNF-alpha and IL-1beta mediate inflammatory hypernociception in mice triggered by B1 but not B2 kinin receptor.

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.

Hypernociception elicited by tibio-tarsal joint flexion in mice: a novel experimental arthritis model for pharmacological screening.

Mice have been used as animal model to study mechanisms underlying inflammatory and immune diseases. The present study describes a model of joint inflammation-induced hypernociception to discriminate pharmacological tests in mice. A polypropylene tip probe with a large area (4.