What Are Cytokines?
Cytokine is the general name. Other names for cytokines include lymphokine (cytokines produced by lymphocytes), chemokine (cytokines with chemotactic activities), monokine (cytokines produced by monocytes), and interleukin (cytokines made by one leukocyte and acting on other leukocytes). Cytokines can work on the cells that secrete them (autocrine action), nearby cells (paracrine action), or distant cells in some cases (endocrine action).
It is common for various cell types to release the same cytokine or for each cytokine to act on numerous different cell types (pleiotropy). Due to the fact that cytokines have redundant activities, various cytokines can stimulate the same functions. When one cytokine stimulates the production of additional cytokines by its target cells, a cascade of cytokines is frequently produced. Furthermore, cytokines have both positive and negative effects.
There are pro-inflammatory and anti-inflammatory cytokines. There is strong evidence that certain cytokines and chemokines play a role in developing and maintaining pathologic pain by directly activating nociceptive sensory neurons. The development of contralateral hyperalgesia and allodynia is correlated with the release of specific inflammatory cytokines, which are also involved in nerve injury or inflammation-induced central sensitization.
How Are Cytokines Produced?
Although various cell populations produce cytokines, helper T cells, and macrophages are the primary constituents. Schwann cells, endothelial cells, mast cells and localized or recruited macrophages are involved in the production of cytokines during pathological and physiological processes. In response to a peripheral nerve injury, macrophages and Schwann cells congregate around the injured nerve site and secrete cytokines and particular growth factors needed for nerve regeneration. Both pro-inflammatory and anti-inflammatory cytokines are increased and decreased by localized inflammatory irritation of the dorsal root ganglion (DRG).
The herniated nucleus pulposus, the DRG soma, the spinal cord, and inflamed skin can all produce and release cytokines. Additionally, cytokines can travel retrogradely from the periphery to the DRG and dorsal horn via axonal or non-axonal mechanisms. Here, they can have significant effects on neuronal activity and thus contribute to the etiology of various pathological pain states.
What Are Pro-inflammatory Cytokines?
Proinflammatory cytokines play a role in the induction of inflammatory responses and are primarily produced by activated macrophages. There is strong evidence that certain pro-inflammatory cytokines, including IL-1, IL-6, and TNF-, play a role in the development of pathological pain. Chemotaxis is known to be induced by a variety of cytokines. Chemokines are a specific subclass of structurally related cytokines. It is typically referred to as chemotactic cytokines. These substances are a group of secreted proteins with a low molecular weight that primarily regulate leukocyte activation and migration. However, some of them also have a wide range of other functions. The conserved cysteine residues in chemokines allow them to be divided into four categories: C-C chemokines (RANTES, monocyte chemoattractant protein or MCP-1, monocyte inflammatory protein or MIP-1), C-X-C chemokines (IL-8, also known as a growth-related oncogene or GRO/KC), C chemokines (lymphotactin), and CXXXC chemokines.
What Are Anti-Inflammatory Cytokines?
The pro-inflammatory cytokine response is regulated by a group of immunoregulatory molecules known as the anti-inflammatory cytokines. Cytokines work with soluble cytokine receptors and particular cytokine inhibitors to control the human immune response. Their physiologic and pathologic roles in systemic inflammatory states are becoming more widely recognized. IL-4, IL-10, IL-11, and IL-13 are important anti-inflammatory cytokines. Interleukin (IL)-1 receptor antagonist is another anti-inflammatory cytokine. Under different conditions, cytokines like leukemia inhibitory factor, interferon-alpha, IL-6, and transforming growth factor (TGF)- are classified as anti-inflammatory or pro-inflammatory. Additionally, certain cytokine receptors for IL-1, TNF-, and IL-18 serve as anti-inflammatory cytokine inhibitors.
What Are the Effects of IL-10?
IL-10 is one of the anti-inflammatory cytokines with the strongest anti-inflammatory effects, inhibiting the expression of pro-inflammatory cytokines by activated macrophages like TNF-, IL-6, and IL-1. In addition, endogenous anti-cytokines and pro-inflammatory cytokine receptors can both be regulated by IL-10. As a result, it has the ability to regulate pro-inflammatory cytokine production and activity at a variety of levels. In numerous animal models, including peripheral neuritis, spinal cord excitotoxic injury, and peripheral nerve injury, acute administration of the IL-10 protein has been shown to suppress the emergence of spinally-mediated pain facilitation.
On the other hand, it has been discovered that blocking spinal IL-10 can stop and even reverse established neuropathic pain behaviors. Recent clinical studies also suggest that low blood levels of the anti-inflammatory cytokines IL-10 and IL-4, found in low concentrations in patients with widespread chronic pain, may be important in developing chronic pain.
What Is the Mechanism of Action?
Certain classes of peripheral and central nervous system neurons may directly modulate the activity of pro-inflammatory cytokines and chemokines. TNF- can be applied topically to the somata of the DRG neurons in vitro or to the peripheral axons in vivo to elicit abnormal spontaneous activity from nociceptive neurons in the peripheral nervous system. TNF- applied topically to the DRG or an autologous HNP extract can both stimulate large, myelinated fast conducting A neurons. TNF- alpha can increase the sensitivity of sensory neurons to the excitation caused by capsaicin, and this increase is probably mediated by prostaglandin production in the neurons. The cAMP-dependent protein kinase (PKA) pathway was discovered to be the mediator of TNF-induced neuronal excitation.
Additionally, TNF-induced cutaneous hypersensitivity to mechanical or thermal stimulation is mediated by the p38 mitogen-activated protein kinase (MAPK). Results from IL-6 knockout mice suggest that IL-6 indirectly influences pain behavior by facilitating sympathetic sprouting in the DRG, which is induced by nerve injury. Recent research has shown that, in the absence of peripheral nerve damage, a localized inflammation of the DRG causes abnormal sympathetic sprouting and up-regulates several pro-inflammatory cytokines, including IL-6. It implies a potential link between sympathetic sprouting and inflammatory responses (two recognized mechanisms linked to a variety of chronic pain states).
Conclusion:
Proinflammatory cytokines contribute to both inflammatory and neuropathic pain development. Anti-inflammatory cytokines could be used for chronic pain treatment, similar to stroke, Alzheimer's, autoimmune diseases, wound healing, and ALS. The hyperexcitability cycle occurring in the sensory neurons would be disrupted by these particular cytokines or antagonists, offering a novel, non-opioid therapeutic strategy for the treatment of pathological pain brought on by inflammation or peripheral nerve injury.
