Inflammatory substances play a part in the modulation of pain by interfering with nociceptive transduction, conduction, and transmission. This modulation may result from alteration of the transcription rate and/or posttranslational changes in proteins involved in the pain pathway. In this review, an important role is assigned to interleukin-6 (IL-6), an inflammatory cytokine, in the physiology of nociception and the pathophysiology of pain. First, IL-6, its receptor gp80, and its transmembranous signal transducer gp130 are upregulated in peripheral nerves, dorsal root ganglia, and the spinal cord during experimental pain. Second, IL-6 modulates the presence of several extracellular and intracellular mediators that are also known to be active during pain. Third, administration of IL-6 alters the responses to thermal or mechanical stimuli and pain in animals. Fourth, neutralizing IL-6 or changes in the IL-6 pathway alter the perception of pain. Although IL-6 is an important factor in the differentiation and survival of neurons and in nerve regeneration, its role in the cascade of chronic pain can compromise any beneficial effect on the patient’s quality of life. As such, IL-6 can be considered an interesting target in the study of pain.
Pain, Inflammatory Agents, and IL-6
Primary- or secondary-order sensory neurons can develop functional, chemical, and structural alterations in response to changes in their environment. These changes can lead to a modification of the transduction, conduction, and transmission functionality of these neurons (1). As a result, the specific role of sensory neurons in mediating normal nociceptive transmission is changed to a new modified condition that contributes to an altered state of sensibility, which is referred to as neural plasticity and pain (1).
With respect to molecular cellular biology, neural plasticity may be the result of changes in the number of one or several functional proteins that occur in turn through long-lasting transcription-dependent changes in the nucleus. In the cytoplasm, some properties of functional proteins can be rapidly changed via posttranslational changes. Cytokines, in addition to other inflammatory agents, influence these intracellular modulating processes. After the cytokine binds to its specific membrane-bound receptor, a cascade of phosphorylation of constitutively expressed signal proteins occurs within the cell. These phosphorylated signal proteins migrate through the cytoplasm and, on the condition that they have a nuclear localization sequence or bind to a protein with such sequence, can reach the nucleus. In the nucleus or cytoplasm, they may influence the transcription rate or induce posttranslational changes. Examples of intracellular signal proteins involved in nociception or pain are mitogen-activated protein kinase (MAPK) (2,3), Ras/Raf, c-jun (4), c-fos (4,5), and signal transducer and activator of transcription (STAT) (3). It is interesting to note that these signal proteins are also involved in the intracellular signal pathways of several cytokines, including IL-6 (6) (Fig. 1).
The human IL-6 gene is located on Chromosome 7 at p21. After an appropriate challenge to an IL-6-producing cell—due to polymorphism of the DNA and posttranslational and postsecretory modifications—multiple isoforms of IL-6 are formed with molecular weight ranging from 21.5 to 28 kDa (7). Clinical implications of the type of IL-6 produced have been described (8). Most, if not all, nucleated cells have been shown to be capable of synthesizing IL-6 in vitro; however, the expression rate of IL-6 is strongly cell dependent.
When IL-6 reaches an IL-6-responsive cell, it binds to its specific receptor IL-6R (gp80). The IL-6/IL-6R complex is responsible for the homodimerization of the transmembranous signal transducer gp130 (Fig. 1). As a result, there is an intracellular cascade of phosphorylation of several signal proteins (6). Two major intracellular cascade systems for IL-6 signaling have been characterized. The classical pathway acts via Janus kinases and STAT factors. A second alternative pathway uses the Ras-dependent MAPK cascade, a pathway that seems to have little relevance to IL-6 signaling under physiological conditions (9). This alternative pathway, however, shares intracellular signal proteins that result in nociceptive potentiation (2–5) (Fig. 1).
Members of the “IL-6 cytokine family,” including IL-11, ciliary neurotrophic factor, oncostatin M, and leukemia-inhibiting factor, share the transmembranous signal transducer gp130 (6). These cytokines are redundant: hence, they induce similar physiologic effects. IL-6R is the unique ligand for IL-6. The other members of the IL-6 family use other receptors for binding, but all require gp130 for signaling (Table 1).
Several cytokines, including IL-1, tumor necrosis factor (TNF), IL-6, and IL-10, are thought to influence nociception or pain (10). Given the above-mentioned posttranslational or transcriptional alterations of proteins during pain and, further, given the properties of IL-6 in the cellular molecular biology, IL-6 is a good candidate as a mediator in the cascade of pain.
Localization of IL-6 in Nervous Tissue— Correlation with Pain Intensity
IL-6-like immunoreactivity was found in the peripheral nerves in normal and inflamed human skin (11). IL-6 or IL-6 messenger RNA (mRNA) was hardly detected in normal sciatic nerves (12,13) or dorsal root ganglia (DRG) (14,15) but were discovered to increase with age (16,17). Only small amounts of IL-6 or IL-6 mRNA were observed in the dorsal or ventral horns of the spinal cord (18,19). The peripheral nociceptors lack IL-6R but constitutively express gp130 (20). IL-6R expression was observed to a slight degree in the intact nerve (21), with a predominance in Schwann cells (17). In rat DRG neurons, IL-6R increases markedly with age (17).
Within 3 h after a sciatic nerve crush injury, IL-6 was produced distally and proximally to the ipsilateral injured site (12,13) (Table 2). A similar IL-6 increase was found after nerve transsection (12,21). In the distal segment, IL-6 declined rapidly 12 to 24 h after the injury (12,13). In the proximal segment, IL-6 levels were larger and remained so for at least 6 days (12). In the distal segment of transected axons, IL-6 mRNA and IL-6 cannot be transcripted and translated, respectively, because of a lack of DNA. Macrophages or Schwann cells at or near the site of injury were shown to be capable of producing inflammatory cytokines (12,13).
In rats with different forms of mononeuropathy (chronic constriction, crush injury, axotomy, and sham-operated), Cui et al. (22) found a correlation between postoperative mechanical allodynia and the number of IL-6-positive cells in the sciatic nerve measured 14 days after surgery. Rats without evident allodynia and sham-operated rats had the smallest number of IL-6-upregulated cells. Bolin et al. (13) found that after sciatic nerve injury, the contralateral noninjured but sham-operated sciatic nerve expressed a smaller but detectable amount of IL-6, which declined rapidly, disappearing within 6 h. Constriction of the infraorbital trigeminal nerve also resulted in a bilateral upregulation of IL-6 in these nerves from Day 3 to Day 10 (23).
IL-6 receptors also increase after nerve injury. IL-6R mRNA was shown to increase in the distal part soon after sciatic nerve crush, having peaked 2 days after crushing and normalized 28 days after crushing; levels of IL-6R mRNA were five times larger after sciatic nerve transsection but behaved similarly (21). In both cases, the course of IL-6R mRNA was accompanied by an increase in the expression of gp130, but no difference in gp130 mRNA was found after transsection or crush injury of the sciatic nerve (21). The presence of both receptors for IL-6 indicates that IL-6 might play a physiological role under these conditions. The fact that the expression pattern of these receptors differs from that of IL-6 shows that they are regulated by independent mechanisms in injured nerves, although in some tissues IL-6 upregulates gp130 expression (24).
DRGs contain the nucleus of most peripheral sensory neurons, implying the possibility of de novo synthesis of IL-6 or its receptor. In response to a transsection of the sciatic nerve at its origin, IL-6 and IL-6 mRNA were found in medium to large sensory neurons 2 to 4 days later in the ipsilateral, but not the contralateral, corresponding DRG (14). After nerve transsection, IL-6 persists for <8 days in DRG (14,25). Because the number of macrophages invading the DRG is maximal 8 to 16 days after nerve injury, these cells seemed not to be the initial source of IL-6 after nerve trauma. Mast cell degranulating agents injected into an uninjured nerve upregulated IL-6 mRNA in medium to large neurons of the DRG, whereas agents that stabilized mast cells injected 5 days before nerve injury attenuated the induction of IL-6 mRNA (26). In a nerve constriction model, IL-6 and IL-6 mRNA were found in DRG neurons at lesser concentrations, but both persisted longer than in a nerve transsection model (25). The presence of IL-6 in this nerve constriction model correlated well with the duration of hypersensitivity (25). IL-6 mRNA was also induced in DRG neurons after dorsal spinal nerve root transsection, but in fewer neurons than after peripheral nerve transsection (26).
After sciatic nerve injury, IL-6 was found in the corresponding ipsi- and contralateral dorsal and ventral horns, and the increases in IL-6 paralleled pain behaviors over time (18,19,27). Sham-operated animals had no IL-6 increases in the spinal cord. After sciatic cryoneurolysis, IL-6 increased within 3 days in the dorsal and ventral horns, and this IL-6 activity was still present 5 weeks later (18). In the dorsal horn, IL-6 mRNA was found preferentially in the superficial laminae (marginal zone and substantia gelatinosa), where nociceptive fibers terminate (19). The fact that the sciatic nerve is a mixed sensory and motor peripheral nerve explains the increase in IL-6 in both the ventral and the dorsal horn. The fact that mRNA of IL-6 was also found in the spinal neurons contradicts an initial hypothesis (18,28) of retrograde axonal or nonaxonal transport of IL-6 produced by macrophages or Schwann cells in the periphery (19). Both IL-6 and IL-6 mRNA were predominantly found in neurons; however, other cellular sources, such as microglia and astrocytes, were not excluded as far as the production of this cytokine is concerned (18,19). Spinal IL-6 mRNA, spinal IL-6, microglial and astrocyte activation, and pain behavior did not differ in rats that sustained an injury at L5 either proximally or distally to the DRG (29). Adjuvant-induced arthritis in rats also resulted in increased IL-6 and IL-6 mRNA levels in the spinal cord (30). At 3 to 10 days after trigeminus constriction, IL-6 was found bilaterally in the brainstem (23).
Little is known about the regulation of expression of IL-6 in neurons. IL-1β, TNFα, and some undefined factors from mast cells have been reported to stimulate IL-6 synthesis in cortical and sensory neurons (26,31). Prostaglandins (PGs) also upregulate IL-6 synthesis in some tissues. The induction of IL-6 in DRG from injured neurons was triggered by a positive signal from the injury site rather than from loss of retrograde inhibition by molecules released from the distal nerve or target tissues (26). The in vitro finding that IL-6 gene transcription was accelerated after membrane depolarization by a yet-undefined calcium-responsive promotor element (32) should help to clarify the transcription and translation of IL-6 in sciatic nerves, DRG, and spinal cord after nerve injury.
Influence of IL-6 on Neuronal Functioning
The above-mentioned rat studies indicate that, after nerve injury with concomitant neuropathic pain, IL-6 is found in the distal and proximal nerve segments, in DRG, and in the ventral and dorsal horns of the spinal cord. The presence of IL-6 in these places correlates well with pain behavior. In addition, the amount of IL-6R and gp130 on cell membranes increases under this condition, suggesting a physiological role of IL-6. Whatever intracellular pathway of neuromodulation is used, IL-6 might profoundly alter the survival, histological behavior, and functionality of cells that play a part in nociception or pathologic pain. These properties of IL-6 on neurons will now be discussed.
Neuronal Survival and Differentiation In Vitro.
In vitro, IL-6 induces neurite extension in pheochromocytoma 12 cells (33) and will cause these cells to differentiate into the neuronal phenotype. IL-6 increases neuronal survival (16,34) and neurite outgrowth (28,35), especially if IL-6R is added to the neuronal cultures. It has been observed that IL-6 supports the survival of embryonic rat sensory neurons via the production of brain-derived neurotrophic factor (36). Pretreatment of cultured hippocampal neurons with IL-6 protects these cells against glutamate-induced cell death. IL-6 attenuates the neurotoxic effects of N-methyl-d-aspartate (NMDA) on rat striatal cholinergic neurons (37). These effects of IL-6 are thought to develop through the interference of IL-6 with the calcium transport systems (16).
Nerve Regeneration and Neuronal Survival In Vivo.
Sensory axonal regeneration is attenuated in IL-6 knockout mice (38). Systemically administered IL-6 retarded the loss of motoneurons after sciatic nerve transsection (39). Anti-IL-6R retarded the regeneration of axotomized hypoglossal nerves, whereas accelerated regeneration was observed in transgenic mice that constitutively expressed IL-6 and IL-6R (28). In IL-6 knockout mice, neuronal loss in DRG after nerve injury was higher than in wild-type mice (25). These studies indicate a positive effect of IL-6 on neuronal survival and nerve regeneration in vivo. In addition, the quality of nerve repair was IL-6 dependent, because regenerating nerves had reduced conduction velocities in IL-6 knockout mice. This is possibly due to the smaller fiber diameters of the regenerating myelinated axons with respect to the wild-type counterparts (40). It was proposed that neuron-derived IL-6 induces microglial proliferation during regeneration and that this gliosis is required for neuron regeneration to occur (41).
Direct Effect of IL-6 on Neurons.
Some cytokines are involved in synaptic plasticity and hyperexcitability as a result of their ability to produce long-term potentiations (42). Hippocampal slices perfused with IL-6 or taken from mice transgenic for IL-6 showed reduced long-term potentiation and posttetanic potentiation (43,44). The effects of IL-6 on long-term potentiation are thought to require an activation of postsynaptic NMDA or other glutamate receptors and to involve an increase in intracellular calcium concentrations (45). Paired pulsed facilitation was inhibited at larger doses of IL-6, suggesting that IL-6 also acts presynaptically (45) on the mobilization of synaptic vesicles (44). Posttetanic potentiation is believed to involve the recruitment of synaptic vesicles from the reserve pool (44). The concomitant increase in STAT3 levels and inhibition of MAPK production in neuronal tissue by IL-6 had a role in changes in synaptic plasticity (44). It is not known whether these findings can be extrapolated to neurons located in DRG or the spinal cord.
IL-6 and Other Substances with Known Neuroprotective or Neuromodulating Effects.
IL-6 increases nitric oxide production in the hippocampus (46), modulates the effect of NMDA receptor stimulation (37,47), and influences the synthesis of substance P (48) and nerve growth factor (NGF) (37,49–51). NGF induces an upregulation of the IL-6R (51). Some substances are coexpressed with IL-6 by neurons studied in vivo(15). Administration of IL-6 to DRG or into the intact sciatic nerve in vivo triggers the induction of the neuropeptide galanin (16,25,52). With reference to IL-6 and its effect on cyclooxygenase or PG production, it is thought that IL-6 increases PG production directly or via IL-1 (53). A direct positive effect of IL-6 on PG production in cerebral endothelial cells was found (54) but was not confirmed by others (55).
IL-6 and the Opioid System.
IL-6 knockout mice had decreased opioid receptors in the midbrain, larger hypothalamic levels of β-endorphin, and a reduced analgesic response to restraint stress or to the administration of morphine (56). Immune cells found in inflamed tissue contain β-endorphin and enkephalin and their respective mRNAs, indicating that these proteins are synthesized by these cells (57). In inflamed tissue, the administration of IL-6 was analgesic, and this effect was reversed by naloxone, showing that IL-6 induced endorphin or enkephalin release from these inflammatory cells (58). Consequently, it was suggested that IL-6 is involved in the responses to nociceptive stimuli and appropriate modulation of the opioid pathway (56).
IL-6 and the Sympathetic System.
IL-6 and IL-6 mRNA were also shown to be produced by sympathetic neurons (17,26,59). IL-6 administered with soluble IL-6R increased sympathetic neuronal survival and induced synthesis of several neuropeptides and neurotransmitter mRNA by these cells (59).
IL-6 Challenge and Pain
All these in vitro and in vivo results indicate the possibility of a modulating role for IL-6 in nociception or pain. This was further investigated by injecting IL-6 or neutralizing antibodies against IL-6 systemically, peripherally, intrathecally, or intracerebroventricularly in normal or genetically manipulated rodents that were subjected to pain.
No peer-reviewed study has been found that deals with the effect of IV or intraperitoneally administered IL-6 on nociception. In rats, there is some evidence that an increase in plasma IL-6 has no effect on pain (58), whereas other evidence suggests that such an increase has a hyperalgesic effect (60).
IL-6, on the condition that it was injected in combination with IL-6R, sensitized nociceptors to heat (61). Injection of IL-6 in a rat hind paw induced dose-dependent mechanical hyperalgesia in both hind paws, although the effect of smaller doses was greatest in the injected paws (60). This mechanoallodynia, which was maximal with 1 ng of human IL-6, reached a plateau between 2 and 3 h after injection, persisted for at least 6 h, and returned to preinjection values within 24 h. Local pretreatment with indomethacin, but not atenolol, profoundly reduced the hyperalgesia, indicating an interaction with PGs but not with adrenergic agents. The authors attributed the evoked hyperalgesia in the contralateral paw to a systemic distribution of the injected cytokine (60). That IL-6 plays a role in pain locally was further shown during inflammatory pain elicited by a carrageenin injection into the hind paw. Local pretreatment with anti-IL-6 antibodies resulted in a reduction of the hyperalgesia in this pain model (60), whereas anti-IL-6 antibodies alone had no effect on nociception (58,60). IL-6 administered 1 wk after injection of Freund’s complete adjuvants into a hind paw resulted in immediate analgesia (<5 min), which was blocked by naloxone, on the condition that IL-6 was injected ipsilaterally but not contralaterally with respect to the Freund’s complete adjuvants. This analgesia for sustained inflammatory pain was attributed to a local release of endogenous opioid peptides by immune cells after IL-6 challenge (58).
In IL-6 knockout mice, in comparison with wild-type mice, the nociceptive response threshold to mechanical and thermal stimulation was lower (hyperalgesia), and hyperalgesia to carrageenin was reduced (62). There was a significant sexual dimorphism with reference to the response to sciatic nerve section in the sense that female IL-6 knockout mice exhibited autonomy, a sign of neuropathic pain, to a much greater extent than male knockout or wild-type mice (62). It would be incautious to attribute all these findings completely to IL-6 depletion, because in this study mice with different genetic backgrounds were used. In IL-6 knockout mice, compensatory mechanisms are developed to overcome the IL-6 absence (63), which possibly also influences the responses to pain. Moreover, the astrocyte and microglial reaction to axotomy and cryoinjury is reduced in these IL-6 knockout mice (64,65). When genetically related wild-type mice were used, these results were not confirmed (25). In this last study, in which chronic constriction of the sciatic nerve was performed, IL-6 knockout mice presented a lesser degree of thermal hyperalgesia and mechanical allodynia, and no algesic differences were found between these mice and nonoperated wild-type animals (25). It is concluded that, at the periphery, IL-6 induces a short-lasting hyperalgesia via the PG pathway. Local analgesia via opioid secretion can be achieved only in the case of inflammatory pain.
IL-6 in DRG.
A decrease in adrenergic sprouting and a decrease in sensory neuron survival in DRGs after sciatic nerve ligation was found in IL-6 knockout mice, with reference to their wild-type parent strain (66). Adrenergic sprouting, which is prevented by sympathectomy, is related to the development of hypersensitivity to mechanical and thermal stimulation (67). Mechanoallodynia, but not thermal allodynia, was profoundly attenuated (and delayed) but not absent in these IL-6 knockout mice, at least for the first 10 days after injury (66). With regard to the effect of IL-6 in DRG, nongenetically manipulated rats with allodynia that subsided after sciatic nerve injury presented less IL-6 expression in the DRG than rats with sustained allodynia after the same procedure (18). All these findings suggest a role for IL-6 in DRG during neuropathic pain.
Intrathecal or Intracerebroventricular IL-6.
Intrathecal IL-6 administration (100 ng in 10 μL) immediately produced touch-evoked but not thermal allodynia in normal rats and produced thermal hyperalgesia but no mechanoallodynia in rats that had previously sustained sciatic cryoneurolytic lesions (18). In the same study, intrathecal IL-6 induced hyperalgesia in the contralateral paw that had not undergone a lesion, but not in control nonoperated animals. This finding implies that IL-6 has a direct nociceptive effect at the spinal level in a previously sensitized spinal cord versus a nonspecific effect that could be related to illness-induced hyperalgesia (18). However, intracerebroventricular injection of IL-6 induced an immediate dose-dependent thermal hyperalgesia for approximately 1 h in rats, which was dependent on PG synthesis (68). Intrathecal administration of neutralizing anti-rat IL-6 antibodies in rats before and after L5 spinal nerve section significantly decreased mechanical allodynia (69). The results of all these experiments speak in favor of a role for IL-6 in noci-transmission through the spinal cord.
Summary of the In Vitro and Animal Studies
IL-6 exerts an initial potential beneficial effect after nerve injury, including protection against neuronal cell death, promotion of growth, and protection against axotomy caused by the nerve injury (19). In this context, an interaction of neurons with adjacent cells, such as Schwann cells and microglia cells, via IL-6 and its receptors seems important. Subsequent detrimental and aberrant sensory effects accompany the IL-6 increase, but further research on the exact role played by IL-6 in the modulation of nociception is warranted.
It should be emphasized that IL-6 is not the only molecule that modulates nociceptive pathways (10). All members of the “IL-6 cytokine family” (Table 1) share the transmembranous signal transducer gp130, resulting in redundancy (21). In addition, IL-1, IL-10, and TNF are other cytokines that might influence pain. Also, other factors, such as glutamine, NGF, substance P, and PGs, each have a specific role in nociception and pain. Only neutralization of the biological effect of a specific factor at a well defined location can unravel the physiological role that the factor exerts at that location. As evidence grows that IL-6 has modulating effects in the cascade of pain at several levels, IL-6 will become an important target in the study of pain.
IL-6 can be blocked by the use of neutralizing antibodies against IL-6 or IL-6R. In addition, several ways of modulating IL-6 signaling have been described. Changes in the number of IL-6R present on the cell membranes can determine the responsiveness of a cell to IL-6. The presence of soluble gp130, the quantity of intracellular suppressors of some phosphorylation cascades, and the quantity of agents that block binding of intracellular signal proteins to DNA, among other factors (70,71), can all attenuate IL-6 signaling.
Clinical Assumptions About the Role of IL-6 on Pain in Humans
There is no clear evidence that IL-6 plays a role in the physiology of pain in humans. Several findings, however, suggest the possibility that IL-6 has a modulating effect on human nociception or pain. Tissue injury elicited by trauma or surgery brings about immediate, well localized pain. This pain is sustained after the initial injury, implying that substances are produced to maintain pain. IL-6 is produced in substantial quantities at the site of a surgical wound (72). IL-6 enters the systemic circulation, where its concentration correlates with the severity of surgery (73) and, thus, with the magnitude of the tissue injury. At 24 to 36 h after surgery, the levels of IL-6 in the plasma reach preoperative values, because its production is attenuated. Postoperative pain behaves like wound or plasma IL-6: intense postoperative pain correlates with the magnitude of tissue injury and subsides days after. On a purely theoretical basis, this can be explained by the described locally or systemically induced hyperalgesic effect of IL-6.
Pentoxifylline is a phosphodiesterase inhibitor that increases cyclic adenosine monophosphate levels in cells, resulting in a nonspecific inhibition of cytokine synthesis (74). The molecule increases the nociceptive threshold for mechanical stimuli in animals (75). If it is given before elective cholecystectomy, patients exhibit smaller IL-6 plasma levels and smaller opioid requirements (75).
Herniated lumbar discs produced spontaneously larger quantities of IL-6, in addition to other inflammatory molecules, than nonherniated controls (76). Nucleus pulposus tissue brought into contact with the L4 and L5 lumbar nerve roots in the rat resulted in an increased IL-6 concentration in that nerve root and DRG 1 to 4 wk later. Mechanical hyperalgesia was observed 3 to 14 days after surgery, suggesting a role for IL-6 in the early stage of herniation-induced sciatic pain (77). Patients with failed back surgery had larger plasma IL-6 levels 8 wk after surgery, and this was accompanied by a more frequent depressive mood, work-related strains, and maladaptive coping strategies (78).
Increasing evidence is available as to the importance of cytokines in acute and particular chronic pain (10). In this context, cytokines can influence transduction, conduction, and transmission of the nociceptive signal, resulting in prolonged or permanent signaling to the brain’s cognitive centers in the absence of a painful noxious or nonnoxious stimulus. IL-6 is an interesting target in the study of pain because this cytokine is synthesized after nerve injury in the peripheral nerves, in DRGs, and in the spinal cord. Administration of IL-6 in the skin provokes pain, and experimental pain increases if IL-6 is injected in the cerebrospinal fluid.
In addition to its beneficial effect on neuronal survival and regeneration, this cytokine might alter the electrophysiological properties of neurons via quantitative or qualitative changes in proteins involved in nociception. The modulating effect of IL-6 on pain is limited in time, and no data are available on the reversibility of the effect. Moreover, the beneficial effect of blocking IL-6 need not be weighed against possible detrimental consequences for the subject. This fact implies that further research is warranted to evaluate the exact role IL-6 plays in pain after various forms of tissue or nerve injury.
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