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Division of Endocrinology, Metabolism, and Molecular Medicine Northwestern University Chicago, Illinois 60611
Address all correspondence and requests for reprints to: William L. Lowe, Jr., M.D., Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University, Feinberg School of Medicine, Tarry 15-703, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail: wlowe{at}northwestern.edu.
Type 1 diabetes is characterized by insulin deficiency secondary to autoimmune-mediated destruction of pancreatic ß-cells (reviewed in Refs. 1 and 2). Two distinguishing features of type 1 diabetes are the presence of autoantibodies and insulitis. Insulitis is characterized by inflammatory infiltrates in the islets consisting primarily of CD8+ but also CD4+ T cells, B cells, macrophages, and natural killer cells. The onset of type 1 diabetes is mediated largely by T cells, although macrophages may also play an important role (2). The importance of T cells was recently demonstrated by a patient with a hereditary deficiency of B cells secondary to X-linked agammaglobulinemia who developed type 1 diabetes (3).
The end result of insulitis in type 1 diabetes is ß-cell death. In rodent models of diabetes, cell death occurs primarily by apoptosis, although necrotic cell death is also evident (1, 2). The primary mode of ß-cell death in humans has not been firmly established. Similarly, the means by which insulitis induces ß-cell death have not been elucidated, although it is likely that soluble mediators, e.g. proinflammatory cytokines, are important. Among the key cytokines are those produced by macrophages, TNF-
and IL-1ß, and by T cells, interferon-
and TNF- (1, 2). A question of obvious importance is the mechanism by which cytokines induce ß-cell dysfunction and death.
As in other cell types, cytokines bind to cell surface receptors on ß-cells, which initiates a cascade of intracellular events. Among the downstream effectors of cytokines in ß-cells are the MAPKs ERK, p38 kinase, and c-Jun N-terminal kinase (c-JNK) (reviewed in Ref. 2). These kinases, in turn, mediate a variety of effects, including activation of transcription factors such as nuclear factor-
B and activator protein-1. The activation of these and other transcription factors, e.g. signal transducer and activator of transcription 1, impacts the expression of genes important for ß-cell function. For example, IL-1ß inhibits the expression of pancreas duodenum homeobox gene-1, which is a transcription factor that regulates the expression of genes such as insulin and glucose transporter 2 (4). Another downstream effect of cytokines in islets is the generation of nitric oxide (NO) and other reactive oxygen species (2). Cytokines increase NO production by both ß-cells and other cell types present in islets, e.g. endothelial cells and macrophages. NO, regardless of its source, is able to induce DNA damage and apoptosis in ß-cells. Despite this well-defined effect of NO, its role in ß-cell dysfunction and death in diabetes is still unclear, as studies supporting and refuting a role for NO in ß-cell death in vivo have been published (1, 2).
One potential confounder regarding the role of NO is the use of in vitro model systems. In this issue of Endocrinology, Todaro et al. (5) have examined the effect of in vivo administration of IL-1ß into the pancreas on islet cell function and death and have compared some of the observed effects to those in islets treated in vitro with IL-1ß. One of the notable distinctions between these two model systems was the effect of IL-1ß on the expression of the gene encoding the inducible form of NO synthase (iNOS). In vivo, iNOS mRNA was undetectable, whereas, in islets treated in vitro with IL-1ß, induction of iNOS mRNA levels was observed. Despite its lack of effect on iNOS expression, in vivo administration of IL-1ß did alter insulin production and increase islet cell caspase activity and apoptosis. The authors suggested that these latter effects were related, in part, to IL-1ß-induced alterations in mitochondrial enzyme activity.
What explains this difference between the effect of IL-1ß administered in vitro and in vivo? This important issue was not addressed in the current study, but there are multiple possible explanations. For one, in vivo injection incorporates the influence of surrounding cell types into the effect of the cytokine, something that may be absent in vitro. For example, islets are highly vascularized via a glomerular-like distribution of blood vessels such that cells are in the immediate proximity of arterial blood (6). Isolation and purification of islets results in disruption of the endogenous vasculature and degeneration and dedifferentiation of endogenous endothelial cells (7). Thus, islets maintained in primary culture are avascular and dependent upon diffusion of oxygen and nutrients into the islet for cell survival and nutrient exchange. Cells within the islet, especially those in the inner core of the islet, are especially vulnerable to ischemia. These differences in the state of the islets in vivo and in vitro undoubtedly influence the response to cytokines.
A second problem introduced by islet purification is disruption of the interaction between islets and their extracellular matrix. In vivo, islets are surrounded by a continuous periinsular basement membrane that contains collagen IV and laminin and is lost during islet purification (8, 9). Within islets, basement membrane is only present around capillaries (9). Multiple studies with islets from diverse species, including pigs, dogs, nonhuman primates, and humans, have demonstrated that islet purification is associated with increased cell death as well as ß-cell dysfunction over the several days following isolation (8, 10, 11, 12, 13, 14). Cell death during this period occurs to a large extent by apoptosis. Indeed, following islet purification, the stress-activated protein kinases c-JNK and p38 kinase are activated, as is caspase 6 (8, 10, 11). Together, these findings suggest that cell death is occurring secondary to anoikis, i.e. cell death secondary to loss of cell-matrix contacts (10, 15, 16). Beyond the impact of the loss of extracellular matrix on the activity of the stress-activated protein kinases, disruption of the matrix may also affect cytokine signaling in ß-cells. Over the last several years, an important role for the extracellular matrix in modulating cellular responses to growth factors has been described (17, 18). This effect is mediated by engagement of adhesion receptors, especially integrins, on the cell surface by molecules in the extracellular matrix. For example, in nonadherent cells, growth factor activation of ERK is transient, whereas, upon engagement of integrins, the activation is more sustained (17, 18). This has important implications for the impact of growth factors on cell proliferation. Similarly, growth factor-induced translocation of ERK to the nucleus, which is important for the phosphorylation of downstream targets such as the transcription factor Elk-1, is also dependent upon cell adhesion (17). Interestingly, cell adhesion is not required for the nuclear translocation of the stress-activated protein kinases c-JNK and p38 kinase (19). The impact of engagement of adhesion receptors on cytokine signaling has not been as well studied, but, recently, the induction of ERK by IL-1ß in chondrocytes exposed to different matrices was examined (20). Similar to findings in growth factor-treated cells, sustained activation of ERK in response to IL-1ß was observed in cells maintained on specific extracellular matrices compared with those grown in simple monolayer on plastic. Whether the extracellular matrix modulates the response of islets to cytokines is not known, but this provides one possible explanation for the differences observed by Todaro et al. (5).
Elucidation of the mechanism by which cytokines and other factors impact cellular function is best accomplished, initially, by use of simple model systems. As illustrated in many systems, however, the effect of growth factors and cytokines is modulated by the microenvironment of the cell, including neighboring cells and the extracellular matrix. Thus, ultimately, studies in vivo must be performed to fully define the impact of cytokines or growth factors on cellular function. Although much remains to be elucidated in terms of the effect of IL-1ß on islet cell function, the study by Todaro et al. (5) provides additional insight into this important issue.
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Received July 15, 2003.
Accepted for publication July 22, 2003.
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B-dependent mechanism. J Cell Biochem 73:321–331[CrossRef][Medline]
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