Rheumatoid arthritis (RA) is a common chronic autoimmune disease leading to significant morbidity and mortality. Various cytokines are involved in RA pathogenesis forming a complex network with multidirectional relationships at different levels. Cytokines probably have a role in all stages of RA development from loss of tolerance to joint localized inflammation and its systemic consequences such as accelerated atherosclerosis. In this chapter, cytokines of different families, such as the TNF superfamily, IL-6 family, IL-10 superfamily, IL-2/ 15 superfamily, and some other cytokines are reviewed. Based on preclinical data and animal models, as well as findings on local expression of cytokines in inflamed joints, many cytokines have been shown to play a role in RA. The most overwhelming evidence comes from clinical studies exploring the efficacy of therapeutic disruption of particular cytokine pathways. To date, the most efficient strategies of anti-cytokine treatment have been the blocking of either TNF-alpha or IL-6. Therefore, these cytokines are currently considered of paramount importance in inflamed synovium. However, the above-mentioned therapeutic approaches are not universally effective, suggesting alternative pathways of regulation in synovial inflammation. Many newer cytokines are being studied in both experimental and clinical settings and, in the future, we hope to gain a greater understanding of the cytokine regulatory network and its interactions in RA.
Type 1 diabetes (T1D) is autoimmune-mediated destruction of pancreatic beta cells resulting in insulin deficiency. Cytokines are vital in diabetes development. They drive the development of autoreactive T cells and are important for activation and maintenance of the autoimmune response. Genetic and cell intrinsic defects in patients with T1D and in animal models of the disease lead to dysregulation of cytokine production and responses, which contributes to loss of immune tolerance and destruction of beta cells. Pro-inflammatory cytokines are produced locally in the islet where they induce expression of thousands of genes, many of which promote islet inflammation. IL-1, TNF and IFN gamma are toxic to beta cells in vitro and have been proposed to contribute to beta cell destruction by mechanisms involving free radical production and endoplasmic reticulum stress. However, in vivo, proinflammatory cytokines are likely to play an immunomodulatory role, increasing beta-cell recognition by T cells and promoting infiltration of macrophages and lymphocytes into the islets. Studying the role of cytokines in T1D has led to identification of important pathways in disease pathogenesis that could be specifically blocked to prevent diabetes.
Insulin resistance is the linchpin for development of the cardiometabolic syndrome and type 2 diabetes. Resistance to the actions of insulin in skeletal muscle is important in development of systemic insulin resistance given that skeletal muscle normally accounts for approximately 75% of all insulin-mediated glucose disposal. However, the molecular mechanisms responsible for skeletal muscle insulin resistance remain poorly defined. Understanding the mechanisms by which skeletal muscle tissue develops resistance to insulin could provide attractive targets for therapeutic interventions. There is emerging evidence of an integral relationship between chronic inflammation, oxidative stress, and skeletal muscle insulin resistance due to circulating inflammatory cytokines derived from adipose tissue (e.g., adipokines) or from local autocrine/paracrine effects of skeletal muscle-derived cytokines (e.g., myokines). This chapter is focused on the effects of inflammatory cytokines and oxidative stress on insulin signaling in skeletal muscle and consequent development of systemic insulin resistance.
This review summarizes our understanding of the role that the cancer cytokine network plays in tumor survival and growth. The tumor cytokine network comprises tumor and stroma-produced factors and receptors. Cytokines produced by tumor cells and stroma cells are critical for tumor cell proliferation and for the formation of neovasculature that provides the oxygen and nutrients necessary for progressive tumor growth. Increasing amounts of experimental evidence indicate that chemotherapeutic drug treatment could stimulate the production of multiple cytokines. This drug-induced cytokine production enrichment is the adaptive response by which tumor cells attempt to protect themselves from the genotoxic stress induced by these drugs. Numerous growth factors and chemokines share angiogenic and growth-stimulating properties; thus, reducing a single factor is insufficient for complete blockage of tumor growth. Instead, a broad disruption of the tumor cytokine network should improve the efficacy of current anticancer strategy. Drug-resistant and self-renewing cancer stem cells (CSCs) are thought to be responsible for the failure of current cancer chemotherapy. CSCs, in comparison to bulk tumor cells, manifest higher levels of growth and angiogenic factor production and over-express certain receptors. Because these characteristics are unique to CSCs, they may be potent targets for cancer therapy. Combining standard chemotherapy with the targeting of specific axes of cytokine network in bulk tumor cells and CSCs could increase the efficacy of cancer therapy.
Alzheimer's disease pathology involves β-amyloid and tau. Various potential pharmacological targets are discussed that may be able to alleviate the accumulation of β-amyloid and tau. Possible causes of Alzheimer's disease are discussed involving impaired glucose and lipid metabolism and obesity. Adipokines may be involved in the etiology of Alzheimer's disease. An extensive discussion of the evidence concerning the adipokines leptin, adiponectin, resistin, visfatin, plasminogen activator inhibitor, interleukin-6 and transforming growth factor β1 as causes of Alzheimer's disease is presented.
