Spinal interleukin‐1β in a mouse model of arthritis and joint pain

Fiorentino, Paolo M; Tallents, Ross H.; Miller, Jen-nie H.; Brouxhon, Sabine M.; O’Banion, M. Kerry; Puzas, J. Edward; Kyrkanides, Stephanos

doi:10.1002/art.23866

Cited by 43 publications

(52 citation statements)

References 22 publications

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“…In agreement with previous studies, 15,40 our data suggest a critical role for central IL-1β in nociceptive signalling during chronic pain states. Greater IL-1RA penetration of the CNS results in greater analgesia and prolonged exposure in the central compartment results in a longer duration of the analgesia induced by the IL-1RA fusion.…”

Section: Discussionsupporting

confidence: 93%

Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti–transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity

Webster

Hatcher

Burrell

et al. 2016

Pain

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Section: Discussionsupporting

confidence: 93%

Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti–transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity

Webster

Hatcher

Burrell

et al. 2016

Pain

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“…We herein showed for the first time that inhibition of CatB activity, either through genetic deletion or via a pharmacological inhibitor significantly reduced the CFA-induced long-lasting tactile allodynia without affecting the CFA-induced paw inflammation. In agreement with the significant reduction of CFA-induced pain hypersensitivity, the production of both mIL-1␤ and mIL-18 was significantly reduced in the spinal microglia of CatBϪ/Ϫ mice, indicating that inflammatory pain is dependent on the production of spinal mIL-1␤ and mIL-18, as has been suggested in previous studies (Guo et al, 2007;Shan et al, 2007;Verri et al, 2007;Fiorentino et al, 2008). Furthermore, a significant reduction of COX-2 was also observed in the spinal dorsal horn neurons of CFA-injected CatBϪ/Ϫ mice.…”

Section: Discussionsupporting

confidence: 90%

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Sun

Hayashi

et al. 2012

J. Neurosci.

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Interleukin (IL)-1␤ and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1␤ and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1␤ and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1␤ expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1␤ and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.

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“…Spinal TNF mRNA levels were increased, and the peaks of these cytokines coincided with the peak of arthritis severity. These data suggest that afferent signaling from joints affected by inflammation may give rise to CNS immune activation, which is similar to findings in other models of joint inflammation (36,37). IL-1β is synthesized as the inactive precursor pro-IL-1β, which is cleaved to the active from by caspase-1 (38).…”

Section: Discussionsupporting

confidence: 83%

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

Lampa

Westman

Kadetoff

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

138

103

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During peripheral immune activation caused by an infection or an inflammatory condition, the innate immune response signals to the brain and causes an up-regulation of central nervous system (CNS) cytokine production. Central actions of proinflammatory cytokines, in particular IL-1β, are pivotal for the induction of fever and fatigue. In the present study, the influence of peripheral chronic joint inflammatory disease in rheumatoid arthritis (RA) on CNS inflammation was investigated. Intrathecal interleukin (IL)-1β concentrations were markedly elevated in RA patients compared with controls or with patients with multiple sclerosis. Conversely, the anti-inflammatory IL-1 receptor antagonist and IL-4 were decreased in RA cerebrospinal fluid (CSF). Tumor necrosis factor and IL-6 levels in the CSF did not differ between patients and controls. Concerning IL-1β, CSF concentrations in RA patients were higher than in serum, indicating local production in the CNS, and there was a positive correlation between CSF IL-1β and fatigue assessments. Next, spinal inflammation in experimental arthritis was investigated. A marked increase of IL-1β, IL-18, and tumor necrosis factor, but not IL-6 mRNA production, in the spinal cord was observed, coinciding with increased arthritis scores in the KBxN serum transfer model. These data provide evidence that peripheral inflammation such as arthritis is associated with an immunological activation in the CNS in both humans and mice, suggesting a possible therapeutic target for centrally affecting conditions as fatigue in chronic inflammatory diseases, for which to date there are no specific treatments.

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Spinal interleukin‐1β in a mouse model of arthritis and joint pain

Cited by 43 publications

References 22 publications

Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti–transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity

Enhanced delivery of IL-1 receptor antagonist to the central nervous system as a novel anti–transferrin receptor-IL-1RA fusion reverses neuropathic mechanical hypersensitivity

Microglial Cathepsin B Contributes to the Initiation of Peripheral Inflammation-Induced Chronic Pain

Peripheral inflammatory disease associated with centrally activated IL-1 system in humans and mice

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