Review
Role of interleukin-1β during pain and inflammation

https://doi.org/10.1016/j.brainresrev.2008.12.020Get rights and content

Abstract

The cytokine cascade in pain and inflammatory processes is a tremendously complex system, involving glial, immune, and neuronal cell interactions. IL-1β is a pro-inflammatory cytokine that has been implicated in pain, inflammation and autoimmune conditions. This review will focus on studies that shed light on the critical role of IL-1β in various pain states, including the role of the intracellular complex, the inflammasome, which regulates IL-1β production. Evidence will be presented demonstrating the importance of IL-1β in both the induction of pain and in the maintenance of pain in chronic states, such as after nerve injury. Additionally, the involvement of IL-1β as a key mediator in the interaction between glia and neurons in pain states will be discussed. Taken together, the evidence presented in the current review showing the importance of IL-1β in animal and human pain states, suggests that blockade of IL-1β be considered as a therapeutic opportunity.

Section snippets

Interleukin-1

Interleukin-1 α and β are prototypic proinflammatory cytokines that exert pleiotrophic effects on a variety of cells and play key roles in acute and chronic inflammatory and autoimmune disorders. There are two IL-1 receptors, IL-1 type 1 receptor (IL-1RI) and IL-1 type 2 receptor (IL-1 RII). IL-1α and IL-1β signal through IL-1RI. Binding to IL-1RII does not lead to cell signaling and it is therefore considered a decoy receptor. Upon binding of IL-1 to IL-1RI, a second receptor termed IL1

Inflammasome

The inflammasome is an intracellular multi-protein complex that is emerging as an important regulator of inflammation (Fig. 1). The inflammasome acts as an activating scaffold for proinflammatory Caspases. One such Caspase, Caspase 1, cleaves and activates pro-IL-1β and pro-IL-18 (reviewed in Martinon and Tschopp, 2007). IL-33 has also been shown to be a possible Caspase 1 substrate (Schmitz et al., 2005). Inflammasomes play important roles in the innate immunity pathway and are active players

IL-1β in gout and other autoinflammatory diseases

Recently, gouty arthritis has taken center stage in the inflammasome field. Gout is one of the most painful acute conditions known to man and has been described since Egyptian times (reviewed in Nuki and Simkin, 2006). Gout is an autoinflammatory disorder that is caused by hyperuricemia. Articular deposits of monosodium urate (MSU) crystals lead to gouty arthritis, which causes acute gout attacks. These attacks present clinically as a highly inflammatory arthritis with intense redness, warmth

IL-1β in the periphery and pain

IL-1β is a potent mechanical and thermal hyperalgesic agent when injected into any number of peripheral tissues (Ferreira et al., 1988, Fukuoka et al., 1994, Watkins et al., 1994, Safieh-Garabedian et al., 1995, Cunha et al., 2000, Zelenka et al., 2005). Intraplantar injection of inflammatory agents, such as carrageenan, lipopolysaccharide (LPS) bacterial endotoxin, or complete Freund's adjuvant (CFA), produce mechanical or thermal hyperalgesia associated with an upregulation of IL-1β and other

IL-1β's role during neuropathic pain

Neuropathic pain arises from dysfunction of the nervous system. The interplay between the immune and nervous systems is thought to be critical for the development and maintenance of neuropathic pain, and the proinflammatory cytokines, including IL-1β, appear to be contributory to the pain state (reviewed in Scholz and Woolf, 2007, Uceyler and Sommer, 2008). Low back pain is a common and debilitating painful disorder which can arise from nerve injury. In degenerate and herniated human

IL-1β in the CNS and pain

As suggested by the spinal cord data mentioned previously, the involvement of cytokines in persistent pain is not limited to peripheral sensitization. Proinflammatory cytokines and their receptors have been found in the CNS. For example, IL-1β's receptor IL-1R1 has been localized to the spinal dorsal horn and brain (Samad et al., 2001, Guo et al., 2007, Zhang et al., 2008).

Direct injection of IL-1β into the CNS has been shown to produce hyperalgesia and enhanced neuronal responses in animals (

IL-1β in central glia-neuronal interaction

Injury-induced central neuronal hyperexcitability, or central sensitization, has been identified as an important mechanism underlying persistent pain. Evidence suggests that glia, particularly astroglia, are intimately involved in the control of neuronal activity (Jourdain et al., 2007, Parri and Crunelli, 2007). Convergent evidence suggests that inflammatory cytokines act as mediators between glia and neurons and assume roles as neuromodulators (reviewed in Watkins and Maier, 2003).

IL-1β signaling, NMDA receptor phosphorylation, and persistent pain

Neuronal glutamate receptors, particularly ionotropic NMDA receptors, play major roles in activity-dependent synaptic plasticity and persistent pain (reviewed in Woolf and Salter, 2000, Guo et al., 2006, Ji and Woolf, 2001). NMDA receptors are heteromers of NR1/NR3 and NR2 subunits (reviewed in Paoletti and Neyton, 2007). Several amino acid residues on the intracellular C-termini of the NR1 and NR2 proteins are phosphorylated upon activation of protein kinases. These phosphorylation sites of

Conclusions

In summary, a growing number of studies show that peripheral injury activates both neuronal and non-neuronal or glial components of the peripheral and central cellular circuitry. The subsequent interactions between the injury site, neurons, and glia cells lead to increased excitability and persistent pain. Proinflammatory cytokines are also induced after injury, and may act on neurons to facilitate central sensitization and hyperalgesia. Recent findings implicate IL-1β in painful and

Acknowledgments

Dr. Ken Ren's work is supported by NIH grants DE11964, DE15374, NS060735. We thank Drs. Susan Croll and Lynn Macdonald for critical reading of this manuscript.

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