proinflammatory cytokines

Proinflammatory cytokines review

Proinflammatory cytokines are a general term for those immunoregulatory cytokines that favour inflammation. The net effect of an inflammatory response is determined by the balance between proinflammatory and anti-inflammatory cytokines. Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. Interleukin (IL)-1 and tumor necrosis factor (TNF) are proinflammatory cytokines, and when they are administered to humans, they produce fever, inflammation, tissue destruction, and, in some cases, shock and death. IL-1 and TNF are inducers of endothelial adhesion molecules, which are essential for the adhesion of leukocytes to the endothelial surface prior to emigration into the tissues. Proinflammatory cytokine-mediated inflammation is a cascade of gene products usually not produced in healthy persons. What triggers the expression of these genes? Although inflammatory products such as endotoxins trigger it, the proinflammatory cytokines IL-1 and TNF (and in some cases IFN-γ) are particularly effective in stimulating the expression of these genes (figure 1). Moreover, IL-1 and TNF act synergistically in this process. Whether induced by an infection, trauma, ischemia, immune-activated T cells, or toxins, IL-1 and TNF initiate the cascade of inflammatory mediators by targeting the endothelium.

Proinflammatory cytokines types

The major proinflammatory cytokines (proinflammatory cytokines list) that are responsible for early responses are IL1-alpha, IL1-beta, IL6, and TNF-alpha. Other proinflammatory mediators include members of the IL20 family, IL33 LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL11, IL12, IL17, IL18, IL8 and a variety of other chemokines that chemoattract inflammatory cells. These cytokines either act as endogenous pyrogens (IL1, IL6, TNF-alpha), upregulate the synthesis of secondary mediators and proinflammatory cytokines by both macrophages and mesenchymal cells (including fibroblasts, epithelial and endothelial cells), stimulate the production of acute phase proteins, or attract inflammatory cells.

Proinflammatory cytokines are involved in pain

There is abundant evidence that certain proinflammatory cytokines such as IL-1β, IL-6, and TNF-α are involved in the process of pathological pain.

Proinflammatory cytokines (e.g., IL-1β, TNF-α) and chemokines (e.g., MCP-1) may directly modulate neuronal activity in various classes of neurons in the peripheral and central nervous system. In the peripheral nervous system, abnormal spontaneous activity can be evoked from nociceptive neurons by topical application of TNF-α to the peripheral axons in vivo, or to the somata of the DRG (dorsal root ganglion) neurons in vitro. Large, myelinated fast conducting Aβ neurons can also be excited by topical application of TNF-α to the DRG or by an autologous HNP extract. TNF-α can enhance the sensitivity of sensory neurons to the excitation produced by capsaicin and this enhancement likely is mediated by the neuronal production of prostaglandins. It was found that TNF-α-induced neuronal excitation is mediated by cAMP-dependent protein kinase (PKA) pathway. The p38 mitogen-activated protein kinase (MAPK) is also involved in TNF-α- induced cutaneous hypersensitivity to mechanical or thermal stimulation. Results obtained from IL-6 knockout mice indicate that IL-6 plays a facilitating role in sympathetic sprouting induced by nerve injury and that its effect on pain behavior is indirectly mediated through sympathetic sprouting in the DRG. Most recently, it is reported that localized inflammation of the DRG up-regulates a number of proinflammatory cytokines including IL-6 and induces abnormal sympathetic sprouting in the absence of peripheral nerve injury. It suggests a possible correlation between inflammatory responses and sympathetic sprouting, which are two well-known mechanisms implicated in various chronic pain states.

Proinflammatory cytokines act as therapeutic target

In summary, proinflammatory cytokines are involved in the development of inflammatory and neuropathic pain. Just as specific cytokines and their neutralizing antibodies have been introduced into clinical trials for the treatment of stroke, Alzheimer's disease, autoimmune diseases, wound healing, and amyotrophic lateral sclerosis, one could utilize local or systemic delivery of anti-inflammatory cytokines or inflammatory cytokine antagonists for the treatment of chronic pain. These specific cytokines or antagonists would act to disrupt the hyperexcitability cycle taking place in the sensory neurons, providing a new, non-opioid therapeutic approach for the treatment of pathological pain due to inflammation or peripheral nerve injury.

Cytokine molecules related

IFN Receptor

IL10 Family Receptor

TGF beta Family Receptor


1, Xie WR, Deng H, Li H, et al. Robust increase of cutaneous sensitivity, cytokine production and sympathetic sprouting in rats with localized inflammatory irritation of the spinal ganglia. Neuroscience 2006;142:809–822. [PubMed: 16887276]
2,DeLeo JA, Colburn RW, Nichols M, et al. Interleukin-6-mediated hyperalgesia/allodynia and increased spinal IL-6 expression in a rat mononeuropathy model. J Interferon Cytokine Res 1996;16:695–700. [PubMed: 8887053]
3, Schafers M, Svensson CI, Sommer C, et al. Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 2003;23:2517–2521. [PubMed: 12684435]
4, Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, et al. Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1.Mediators Inflamm 2006;2006:28398. [PubMed: 16864900]
5, Ozaktay AC, Kallakuri S, Takebayashi T, et al. Effects of interleukin-1 beta, interleukin-6, and tumor necrosis factor on sensitivity of dorsal root ganglion and peripheral receptive fields in rats. Eur SpineJ 2006:1–9.