IL-4, JAK-STAT signaling, and pain

Busch-Dienstfertig, Melanie; González-Rodríguez, Sara

doi:10.4161/jkst.27638

Cited by 51 publications

(44 citation statements)

References 82 publications

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“…We propose that fostering the beneficial effects of intrinsic M2 macrophages is more promising than the general inhibition of neuroinflammation for tackling pathological pain. The actions of IL-4 are believed to be mediated primarily by the inhibition of proinflammatory mediators (2,58). Yet, here we provide evidence that the endogenous opioid system is essential to the actions of IL-4 and M2 macrophages in pain control.…”

Section: Discussionmentioning

confidence: 59%

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Celik¹,

Łabuz²,

Keye³

et al. 2020

JCI Insight

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Section: Discussionmentioning

confidence: 59%

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Celik¹,

Łabuz²,

Keye³

et al. 2020

JCI Insight

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“…However, IL-6 is pleiotropic, so it has both pro- and anti-inflammatory actions including the induction of IL-10 (Opal and DePalo, 2000). Nevertheless, a recent review has concluded that there are no reports of IL-6 showing direct anti-nociceptive properties (Busch-Dienstfertig and González-Rodríguez, 2013). Based on our data, this Th1/Th2 dysregulation is plausible since the magnitude of IL-10 induction was greater than IL-6 and remained significantly elevated in older, but not younger adults.…”

Section: Discussionmentioning

confidence: 99%

Age differences in cytokine expression under conditions of health using experimental pain models

Cruz-Almeida

Aguirre²,

Sorenson³

et al. 2015

Experimental Gerontology

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Older adults are at an increased risk to develop frequent and prolonged pain. Emerging evidence proposes a link between immune changes and pain, which is consistent with the inflammation theory of aging and the increased incidence of age-related diseases. This study tested the hypothesis that older adults show greater immune responses to experimental pain compared to younger individuals. Study subjects (8 younger and 9 older healthy adults) underwent 3 experimental sessions using well-validated human experimental pain models: the cold pressor task (CPT), focal heat pain (FHP), and a non-painful thermal control. Blood was collected through an indwelling catheter at baseline and 3, 15, 30, 45, 60, and 90 minutes post-stimuli administration. Pro-inflammatory cytokines (TNF-α IL-6 and IL-8) peaked at the same time points for both groups, with greater elevations among older subjects for TNF-α and IL-8 in both pain models and elevations in IL-6 only for CPT. Antiinflammatory cytokines (IL-4, IL-5, and IL-10) generally peaked later for the older subjects, with increased elevations for FHP but not the CPT. These data is consistent with the assertion that agerelated immune system dysregulation may account for the increased prevalence of pain in older adults.

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“…After receptor ligation, the JAK proteins are phosphorylated, and activated JAKs then phosphorylate STAT monomers, leading to dimerization, nuclear translocation, and DNA binding. Although there are four JAKs (JAK1, JAK2, JAK3, and TYK2) and seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6) in mammals, the number of potential combinations alone does not fully explain the pleiotropy in signaling (22,34,132). For example, IL-6R and IL-10R signaling both result in STAT3 activation through JAK activation; however, one cytokine is mostly proinflammatory, and the other is considered anti-inflammatory.…”

Section: Jak/stat Signalingmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

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IL-4, JAK-STAT signaling, and pain

Cited by 51 publications

References 82 publications

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

IL-4 induces M2 macrophages to produce sustained analgesia via opioids

Age differences in cytokine expression under conditions of health using experimental pain models

Neuraxial Cytokines in Pain States

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