*3.3.4 Role of pro-inflammatory cytokines in apoptosis-mediated b-cell death*

It should be emphasized that TNF-α is a pleiotropic cytokine that plays a key role in many physiological and pathological cellular processes, including the role of an inducer of activation apoptosis of target cells [61]. It was believed that TNF-α could directly destroy b-cells, since it contains a death domain in its receptor. However, experimental studies using b-cell culture have shown that this is not the case. It turned out that in the presence of TNF-α, NF-kB (Nuclear Factor of κ-chain B-lymphocytes) which is known for its antiapoptotic properties, is activated [56, 62]. This is supported by in vivo experimental studies using NOD mice indicating that

*The Role of Apoptosis in Autoimmune Destruction of Pancreatic b-Cells DOI: http://dx.doi.org/10.5772/intechopen.108290*

inhibition of NF-kB in b-cells increases their susceptibility to TNF-α-mediated apoptosis [62, 63].

Recent studies show that the priority of the latest therapeutic developments in the field of type 1 diabetes is the suppression of inflammation in the target organ. Resolvin D1 has been shown to reduce the severity of streptozotocin-induced T1DM by reducing oxidative stress and suppressing inflammation. The action of the drug is largely aimed at suppressing the production of pro-inflammatory cytokines TNF-α and IL-6. As a result of the action of Resolvin D1 in the peripheral blood of experimental animals, a statistically significant decrease in the concentration of TNF-α and IL-6 was recorded compared to the initial values (p < 0.001) [5]. In another study, the use of immunomodulatory therapy in individuals with a high risk of developing type 1 diabetes contributed to the suppression of the production of TNF-α and IFN-g, in combination with an increase in the concentration of C-peptide compared to pretreatment levels. Teplizumab treatment improved b-cell function, as evidenced by a quantitative and qualitative improvement in insulin secretion [64]. Thus, monitoring of the cytokine profile and timely therapy aimed at suppressing anti-inflammatory cytokines is of critical importance in the pre-diabetic stage. New approaches to preventing the progression of clinical T1DM. to irreversible destruction of b-cells and insulin deficiency are a promising direction in modern diabetology.

IL-1b, produced by macrophages, also plays a significant role in the destruction of b-cells. It has been established that after stimulation of pancreatic b-cells in vitro with IL-1b, the expression of Fas receptors increases on their surface, as a result of which b-cells become targets for T-lymphocytes carrying FasL [1]. Expression of Fas receptors by b-cells has been confirmed not only by in vitro studies, but also in vivo in experiments using laboratory animals [1, 6]. Thus, IL-1b is involved in the destruction of b-cells by stimulating the expression of the Fas receptor on the membranes of b-cells. In b-cells after their interaction with IL-1b, characteristic signs of apoptosis are revealed: DNA fragmentation, nuclear condensation and the formation of apoptotic bodies [65].

IFN-g usually acts in combination with other pro-inflammatory cytokines, such as TNF-a or IL-1b, and sometimes both. IFN-g stimulates the production of IL-1b APC [66]. When IFN-g and TNF-a bind to cognate receptors on b-cells, either caspasedependent b-cell apoptosis is triggered or b-cell apoptotic death is activated by inducible NO synthase (iNOS) [62]. The triad of pro-inflammatory cytokines TNF-a, IFN-g, and IL-1b is detrimental to b-cells, since it promotes the triggering of various mechanisms of apoptotic death of the islets of Langerhans. Maintaining high concentrations of all three cytokines in the microenvironment of b-cells enhances their apoptotic death [67].

Thus, many signaling proteins are involved in the apoptotic death of b-cells in T1DM, each of which can become a potential therapeutic target in the development of new methods of therapy for this disease.

A general scheme of the mechanisms of apoptotic death of b-cells in T1DM is shown in **Figure 3**.

The B-cell antigen is captured by antigen-presenting cells (APCs). Antigen processing results in the formation of antigenic fragments that form a complex with MHC II. The antigen-MHC II complex is recognized by T cell receptors (TCRs). T-cell activation occurs due to antigen recognition and co-stimulation by secondary signals of costimulatory molecules—CD28-B7. An activated cytotoxic T lymphocyte (CD8+CTL) produces IFN-g, which subsequently stimulates APC to produce additional cytokines IL-1b and TNF-a. In addition, CD8+CTL produces proteins: granzyme B and perforin.

**Figure 3.** *The main mechanisms of pancreatic b-cells apoptosis in T1DM.*

IL-1b increases expression of the Fas receptor on b-cells, which increases their sensitivity to Fas-mediated apoptosis mediated by CD8+ and CD4+ T cells. Conversely, regulatory T cells (T-regs) suppress CD8+ and CD4+ T cells [1].
