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. 2010 Oct 4:6:63.
doi: 10.1186/1744-8069-6-63.

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

Thiago M Cunha  1 , Jhimmy Talbot, Larissa G Pinto, Silvio M Vieira, Guilherme R Souza, Ana T Guerrero, Fabiane Sonego, Waldiceu A Verri Jr, Dario S Zamboni, Sergio H Ferreira, Fernando Q Cunha
Affiliations

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

Thiago M Cunha et al. Mol Pain. .

Abstract

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-/-).

Results: Mechanical inflammatory hypernociception was evaluated using an electronic version of the von Frey test. The production of cytokines, PGE₂ and neutrophil migration were evaluated by ELISA, radioimmunoassay and myeloperoxidase activity, respectively. The interleukin (IL)-1β and cyclooxygenase (COX)-2 protein expression were evaluated by western blotting. The mechanical hypernociception induced by intraplantar injection of carrageenin, tumour necrosis factor (TNF)α and CXCL1/KC was reduced in casp1-/- mice compared with WT mice. However, the hypernociception induced by IL-1β and PGE₂ did not differ in WT and casp1-/- mice. Carrageenin-induced TNF-α and CXCL1/KC production and neutrophil recruitment in the paws of WT mice were not different from casp1-/- mice, while the maturation of IL-1β was reduced in casp1-/- mice. Furthermore, carrageenin induced an increase in the expression of COX-2 and PGE₂ production in the paw of WT mice, but was reduced in casp1-/- mice.

Conclusion: These results suggest that caspase-1 plays a critical role in the cascade of events involved in the genesis of inflammatory hypernociception by promoting IL-1β maturation. Because caspase-1 is involved in the induction of COX-2 expression and PGE₂ production, our data support the assertion that caspase-1 is a key target to control inflammatory pain.

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Figures

Figure 1
Figure 1
The involvement of caspase-1 in mechanical inflammatory hypernociception. (A) Mechanical nociceptive threshold of wild type and casp1-/- mice using the electronic von Frey. (B) Wild type or casp1-/- mice received an intraplantar injection of carrageenin (100 μg/paw). Mechanical hypernociception was evaluated 3 and 5 h after carrageenin injection. (C) Mice were pretreated with a caspase-1 inhibitor (YVAD-CMK, 1-9 mg/kg s.c. 30 min before) followed by intraplantar injection of carrageenin (100 μg/paw). Mechanical hypernociception was evaluated 3 h after carrageenin injection. Data are expressed as the mean ± S.E.M. of 5 animals per group. * indicates statistical significance compared to the saline injected group; # statistical significance compared to wild type or vehicle-treated group. P < 0.05, one-way ANOVA followed by the Bonferroni's test.
Figure 2
Figure 2
Role of neutrophils and cytokines in caspase-1 mediation of inflammatory hypernociception. (A-B) Wild type and casp1-/- mice received an intraplantar injection of carrageenin or saline. After 3 h, plantar tissue samples were removed and the levels of TNF-α and CXCL1/KC were determined by ELISA. (C) At 3 h after carrageenin injection, the activity of MPO was determined in the mice paw skin of wild type and casp1-/- mice as an index of neutrophil migration. Data are expressed as the mean ± S.E.M. of 5 animals per group. * indicates statistical significance compared to the saline-injected group. P < 0.05, one-way ANOVA followed by the Bonferroni's test.
Figure 3
Figure 3
Role of caspase-1 in the mechanical hypernociception induced by pro-nociceptive cytokines and PGE2. (A) Wild type or casp1-/- mice received an intraplantar injection of TNF-α (100 pg/paw), CXCL1/KC (10 ng/paw or IL-1β (1 ng/paw). Mechanical hypernociception was evaluated 3 h after cytokines injection. (B) Wild type or casp1-/- mice received and intraplantar injection of PGE2 (100 ng/paw). Mechanical hypernociception was evaluated 0.5, 1.0, and 1.5 h after PGE2 injection. Data are expressed as the mean ± S.E.M. of 5 animals per group. * indicates statistical significance compared to the saline-injected group; # indicates statistical significance compared to wild type group. P < 0.05, one-way ANOVA followed by the Bonferroni's test.
Figure 4
Figure 4
IL-1β maturation, but not maturation of IL-18, is involved in caspase-1 mediation of inflammatory hypernociception. (A) Wild type or IL-18-/- mice received an intraplantar injection of carrageenin (100 μg/paw). Mechanical hypernociception was evaluated 3 h after carrageenin injection. Mice were pretreated with IL-1ra (3-90 mg/kg, i.v. 15 min before carrageenin injection) followed by intraplantar injection of carrageenin (100 μg/paw). Mechanical hypernociception was evaluated 3 h after carrageenin injection. (C) After the determination of hypernociception, mice paw skins were removed and the activity of MPO was determined. (D) Wild type and casp1-/- mice received an intraplantar injection of carrageenin or saline. After 1.5 h, plantar tissue samples were removed and the level of pro-IL-1β mRNA was determined by real-time PCR. (D) Wild type and casp1-/- mice received an intraplantar injection of carrageenin or saline. After 3 h, plantar tissue samples were removed and the level of mature IL-1β (~19 kDa) was determined by western blot. The β-actin level was used as a control. Data are presented as representative blots. Densitometry of the pixel intensity of IL-1β bands relative to β-actin is present. Data are expressed as the mean ± S.E.M. of 5 animals per group. * indicates statistical significance compared to the saline-injected group; # indicates statistical significance compared to the vehicle-treated group or wild type mice group. P < 0.05, one-way ANOVA followed by the Bonferroni's test.
Figure 5
Figure 5
Role of caspase-1 in the induction of COX-2 and prostaglandin production during carrageenin-induced inflammation. (A) Wild type and casp1-/- mice received an intraplantar injection of carrageenin (100 μ/paw) or saline. After 3 h, plantar tissue samples were removed and the expression of COX-2 was determined by western blot. The β-actin level was used as a control. Data are presented as representative blots. (B) Densitometry of the pixel intensity of COX-2 bands relative to β-actin is present. (C) Wild type and casp1-/- mice received an intraplantar injection of carrageenin (100 μ/paw) or saline. After 3 h, plantar tissue samples were removed and the level of PGE2 was determined by RIA. Data are expressed as the mean ± S.E.M. of 5 animals per group. * indicates statistical significance compared to the saline-injected group; # indicates statistical significance compared to the wild type group. P < 0.05, one-way ANOVA followed by the Bonferroni's test.
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