The Dark Side of Cytokines

Cytokines have been implicated in a variety of physiological processes involving lymphoid tissue development, lymphocyte activation, and control of regenerative processes such as wound healing. The first characterization of a cytokine implicated in abolishing or killing tumor cells – the tumor necrosis factor (TNF) – fostered and boosted a completely new field of research that in addition to cancer research started to generate an overwhelming amount of knowledge in immunology, various pathological processes, and other fields of research. Due to the complex networks and versatile functions of cytokines, it soon became clear that cytokines can possess diametric functions in various biological processes. As for tumor research it was shown that some cytokines – depending on the type of organ, the time of action, gender, and the cellular environment – can have either proor anticarcinogenic action. For those cytokines reported to be procarcinogenic, this could be accomplished by directly acting as oncogenes or generating an inflammatory environment that is procarcinogenic. Here we review a novel role Mathias Heikenwälder, PhD Institute of Virology, TU Munich Schneckenburgerstr. 8 DE–81675 Munich (Germany) Tel. +49 89 4140 7440, E-Mail heikenwaelder @ helmholtz-muenchen.de © 2012 S. Karger AG, Basel 0257–2753/12/0305–0453$38.00/0 Accessible online at: www.karger.com/ddi Bauer /Namineni /Reisinger /Zöller /Yuan / Heikenwälder Dig Dis 2012;30:453–468 454 ogy by deviating the study of inflammation from a traditional viewpoint which surrounds the four cardinal signs of inflammation [1] . The Inflammatory Types: Acute and Chronic Phases In the recent past, there has been a tremendous increase in our understanding of inflammation, which has led to its division into acute and chronic phases. Acute Phase Typically, an inflammation is triggered either by a mechanical tissue injury or by recognition of pathogens like bacteria and viruses through pattern recognition receptors such as Toll-like receptors (TLRs) present on innate immune cells leading to the production of inflammatory cytokines and chemokines such as tumor necrosis factor (TNF), IL-1, IL-6, IL-8, IL-11, CCL2, and CXCL8. Their activity in turn mediates inflammation by attraction of lymphocytes and monocytes. Among these, IL-1 and TNF are the most potent inflammatory molecules mediating acute inflammation, e.g. induced by lipopolysaccharide (LPS), and they are the primary cause of septic shock. In the liver, IL-1, IL-6, and TNF are shown to have systemic effects when secreted in sufficient amounts by inducing hepatocytes to produce acute-phase proteins such as C-reactive protein (CRP) and coagulation factors. These mediators activate brain endothelium to secrete prostaglandins such as PGE2 which in turn induce specific neuronal populations in the CNS to promote a sickness behavior characterized by fever, anorexia, fatigue, sleepiness, and social withdrawal [2] . Mechanical tissue injury in the absence of infection also leads to acute inflammation which promotes tissue repair and helps prevent colonization of damaged tissues by opportunistic pathogens. Tissue damage is recognized by nociceptors which induce a pain sensation by exudate formation and tissue swelling in the affected area. Prostaglandins lower the threshold of pain sensations by increasing the sensitivity of nociceptors. In this situation, the innate immune cells such as resident macrophages induce reparative responses. The sensing of the inflammatory milieu by the vagus nerve triggers an ‘inflammatory reflex’, which is involved in the negative control of inflammation [1, 3] . Chronic Phase Failure to resolve acute inflammation resulting from immune responses to pathogens can lead to a persistent chronic inflammation which may last weeks or months and in some instances years. Cytokine interactions and infiltration of lymphocytes during this phase of inflammation lead to monocyte chemotaxis to the site of inflammation where resident macrophages are activated by interferon (IFN) and MCP-1. These activated macrophages are restricted to the sites of inflammation by migration inhibition factors such as GM-CSF and IFNwhich leads to an elevation in the levels of IL-1 and TNF. In case of chronic inflammation, cytokines such as IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, and TGFare known to promote humoral inflammation whereas IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, IFNs, IFN -inducing factor (IGIF), TGF, TNF, and lymphotoxin (LT) are known to promote cellular inflammation [4] . These prolonged inflammatory signals can lead to the formation of granulomas and the generation of tertiary lymphoid organs (TLO) at the site of infection and in some cases might lead or contribute to certain diseases such as obesity, chronic obstructive pulmonary disease (COPD), autoimmune pancreatitis, type 2 diabetes, atherosclerosis, neurodegenerative diseases, and cancer [1] . Factors Influencing Inflammation Leading to Cancer In 1863, Rudolf Virchow noticed the presence of leukocytes in neoplastic tissues and suggested that the ‘lymphoreticular infiltrate’ reflected the origin of cancer at sites of chronic inflammation. This was the first observation linking inflammation and cancer. A lot of evidence later supported Virchow’s observations and we now know of a large set of factors ranging from bacteria, viruses, and environmental factors. Dietary components are also shown to promote a chronic inflammatory state which ultimately leads to cancer. In the recent past, molecular mechanisms linking inflammation and cancer have been established which led to the proposal of an inflammatory microenvironment as the seventh hallmark of cancer [5, 6] . Infectious Agents In appreciation of the work involving the identification of infectious agents causing cancer, the Nobel Prize was awarded in 2005 to Barry Marshal and Robin Warren for elucidating the role of Helicobacter pylori in gastritis and peptic ulcers and to Harald zu Hausen for his discovery that human papilloma viruses are the caus-