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• W2079234429 abstract "In this issue of Immunological Reviews, articles are presented that cover many aspects of the newer biology of cytokines. It has been almost 50 years since the description of the interferons (IFNs) first hinted at the complex biology that formed the basis for immunity to infection. Since then, the field has moved through the description and characterization of macrophage-activating and inhibitory factors and various soluble mediators that influenced T- and B-cell behaviors. Even at these early points, the potential of the use of cytokines or cytokine antagonists as treatments to augment immunity, prevent immune hyperactivity, or influence the type of response was apparent and formed the basis for several of the early biotech companies. The pace accelerated through the 1980s with the application of molecular approaches to understand the basis for these activities, and the cloning of genes for numerous cytokines, costimulatory molecules, and death receptors started to reveal the molecular interactions that underpinned immunity. For example, the ability to study cytokine production provided the basis for the description of T-helper 1 (Th1) and Th2 subsets (1), and a framework emerged that allowed immunologists to probe models of how the immune system functioned during inflammation and how inappropriate immune responses could lead to disease. With the start of various genome projects in the 1990s, discovery-based programs intensified to a point where the list of interleukins (ILs), chemokines, tumor necrosis factor (TNF), and IFN family members was almost matched by the numbers of pattern recognition receptors that provided the foundation for the development of innate and adaptive responses. At this point, it seemed that with all this information and several dominant paradigms in place to explain how the immune system worked during inflammation, it was only a matter of time before this was translated into the development of new therapies to manage a spectrum of immune-mediated diseases. However, the challenge that then emerged was not discovering but rather understanding the biology of these factors. This point is illustrated by IL-1, IL-2, and the IFNs, which represent some of the best-studied cytokines, and all of which are either targets for intervention or are used therapeutically. However, the IL-1 family has been expanded to include IL-18 and IL-33, and Luke O'Neil (2) highlights newer insights into their biology of how they signal. Our understanding of the complex properties of IL-2 continues to grow, and Abbas and colleagues (3) highlight how IL-2 has transformed from being a major T-cell growth factor into a cytokine that promotes regulatory T-cell (Treg) development and expansion and thereby contributes to the maintenance of immune homeostasis. While the study of the type I IFNs is a mature field, the article by Casanova et al. (4) illustrates how important the factors are to human disease. They perform an extensive overview of the human mutants in cytokine biology that have provided absolutely fundamental insights into the role of the IFNs in immunity. In contrast, Lionel Ivashkiv and his co-authors (5) focus on some of the more nuanced aspects of how the IFNs influence human macrophages. Recent advances in many areas of cytokine biology have also resulted in the modification of existing paradigms for the generation of new models to better explain the homeostatic mechanism that allows the immune system to function. Prominent examples include the return of Tregs to the immunological mainstream (6) and the rise of pattern recognition receptors as the foundations of innate and adaptive immunity (7). More recently, the description of the Th17 subset and their association with a variety of disease conditions that range from cancer to almost every T-cell-mediated inflammatory condition have attracted unprecedented levels of interest. This interest is certainly reflected in the reviews presented in this issue, as, without exception, all refer at some point to Th17 cells. Indeed, several articles are specifically focused on these populations or the biology of IL-17 family members. Thus, in complementary pieces, Iwakura et al. (8) and Chen Dong (9) place an emphasis on IL-17 and areas of debate on its function that have arisen from different experimental models. Fouser et al. (10) stress elements of the structural biology that underlie how IL-17A and IL-17F interact to form different dimers as well as the factors that affect the ability of these cells to produce IL-21 and IL-22. The murine system remains the premier experimental model for basic immunologists, and Tato and Cua (11) review how the comparison of the IL-12- and IL-23-deficient mice has allowed a better understanding of the function of IL-23 in autoimmunity. They also provide an overview of some of the paradoxes that pertain to IL-23, which still need to be addressed. Nevertheless, applying this information to a more biologically relevant system is going to be necessary, and Trinchieri et al. (12), in their article on the regulation of IL-12 family members, have provided a call to arms for increased emphasis on human immunology to allow translation into viable therapies. It is fortuitous that trials that were originally designed to target IL-12p40 and block inappropriate Th1 responses have proven useful in at least one clinical setting that we now associate with hyperactive Th17 activity. Thus, de Waal Malefyt et al. (13) evaluate the many factors, including IL-23, that promote human Th17 cells and review the data that implicate a role for IL-23 in the setting of psoriasis and highlight how the use of anti-IL-12p40 has moved rapidly from experimental biology (14) into clinically relevant therapy (15, 16). Given the data that link IL-12 to tumor surveillance and IL-23 to the promotion of cancer (17), there are general concerns about whether long-term blockade of IL-12 and/or IL-23 renders patients more susceptible to neoplasms or opportunistic infections, and monitoring of the effects of these treatments will provide a fuller picture of the costs and benefits. As part of efforts to better understand the ‘when and where’ of cytokine biology, we as a community may need to consider organ-based effects. Thus, the effects of a particular cytokine in one tissue may be dramatically altered in a different microenvironment. Several articles in this issue highlight barrier functions at mucosal surfaces. Powrie (18) and Kolls (19) and their colleagues discuss the biology of IL-23 and Th17 cells in the context of inappropriate inflammation (18) or anti-pathogen responses (19) in the gut. In contrast, Artis et al. (20) focus on how a trinity of newer cytokines [thymic stromal lymphopoietin (TSLP), IL-25, and IL-33] influence Th2 cells and some of the unique elements of barrier sites that affect T-helper responses. The review by Cooper and Khader (21) on resistance to tuberculosis incorporates many elements of the newer cytokine biology but highlights some of the challenges faced for any single pathogen when attempting to determine which of these networks are biologically relevant. From an academic and more applied perspective, another important area is understanding the endogenous mechanisms that limit inflammation. IL-10 has long been recognized as an important inhibitor of cell-mediated immunity (22), and Mosser and Zhang (23) highlight the progress in understanding the molecular events that regulate its production. However, almost 20 years after the description of its biological activity (24), we still have a limited understanding of how IL-10 mediates its inhibitory effects. In contrast, Maynard and Weaver (25) discuss the literature that illustrates that essentially every major peripheral T-cell subset is capable of producing IL-10. Making biological sense of this observation and understanding the factors that promote IL-10 in diverse T-cell subsets provides a real challenge to our community. More recently, IL-27 has been recognized as an additional suppressor of the immune system, and Yoshida (26) contrasts the pro- and anti-inflammatory effects of this heterodimer and its link to the production of IL-10. That article is complemented by the comments of Collison and Vignali (27), who highlight the newest kid on the block, IL-35. This heterodimeric cytokine is composed of IL-12 and IL-27 subunits, and its description will certainly influence the interpretation of data generated in IL-12p35 and IL-27EBI-3 knockout mice. So, where to next? Through reviewing these articles, it is amazing how far cytokine biology has come in the last 50 years to the current status of defined cytokine-induced master regulators of cell fate and the balkanization of every conceivable immune subset and new paradigms that have been developed (28). While the emphasis in this issue is on Th17 cells, they really only represent a proportion of the opportunities to design therapies that will not only influence T-helper cell polarization but also the migration, expansion, contraction, and survival of these potentially damaging cells. Indeed, there are already signs that Th17 cells are not the cause of all pathology (and in fact promote barrier function) and that Th1-like cells still have a role in many disease processes. The process of understanding what different cytokines and T-helper subsets do will be an iterative process and will require the modification of many of our current models. One theme that has emerged is that the activities of individual cytokines are going to be context specific, varying with sites such as gut versus skin, effects on different cell types, and distinct roles in different inflammatory conditions. With this in mind, a better understanding of disease in an individual can determine which immune-modulatory strategies are most likely to be effective. This approach is best illustrated in the cancer field with the development of treatments based on molecular profiling of tumors. The opportunity to compare the molecular profiles of the types of inflammation in individuals that do or do not respond to current treatments (anti-TNF, IL-1RA, or anti-IL-12p40) should lead to a better understanding of the basis for these variations and may ultimately allow more informed tailoring of treatments to affected patients. In addition, there are already signs of advances in other basic areas of biology that will impact on understanding how cytokine expression is regulated or how these factors function. Prominent examples include the role of microRNA in the regulation of cytokine mRNA expression (29) as well as the influence of cell division in the generation of T-cell diversity (30) and evidence that certain cytokine/cytokine receptor complexes can localize to the nucleus and have transcriptional activities (31). Whether these subjects become ‘hot topics’ is uncertain, but it seems likely that new advances in these areas will alter our perceptions of how inflammation develops or resolves." @default.
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• W2079234429 title "New paradigms in inflammation: where to next?" @default.
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