How Stress Prevents Immunostimulatory Effects Interleukin-12

How Stress Prevents the Immunostimulatory Effects of Interleukin-12

How Stress Prevents – Effects of Interleukin-12

A new study published in the journal Brain, Behavior, and Immunity suggests that chronic stress exposure can prevent the effects of immunostimulatory treatments such as the administration of interleukin (IL)-12, which is independent from the stress effects on baseline immune measures.

Immune stimulation by cytokines or other biological response modifiers (BRMs) is a common approach in the field of tumor immunotherapy.

Type 1 T-helper (Th)1 and proinflammatory cytokines are major activators of Th1-dependent cellular immunity, and anti-tumor effects of IL-12 are reported in various animal models.

IL-12 is one of the vastly investigated cytokines in this context, being a major TH1 differentiation and cellular immunity inducer. Its ligation to the IL-12 receptor (IL-12R), results in a signal transduction that activates STAT4, which mediates most of IL-12’s biological activities through the production of IFN-γ.

Thus, a remarkable function of IL12 is its ability to induce IFNγ release from natural killer (NK) cells as well as CD4+ and CD8+ T cells (see cover image). In fact, IL12 signaling via STAT-4 is critical for Th1 differentiation and acquisition of cytolytic functions by CD8+ T cells.

Despite these promising beneficial effects of IL-12 in the context of cancer immunotherapy and surgery, the use of IL-12 in the clinical settings, however, has yielded rather limited results. A factor that may contribute to this discrepancy is the environmental and psychological state that characterizes cancer patients.

Stress hormones may limit the capacity of IL-12 and other BRMs to activate immunocytes, or may prevent activated immunocytes from exerting their beneficial effects. Despite the potential clinical implication, this hypothesis has rarely been addressed by animal or human studies. In fact, little is known about the specific impact of stress responses on the efficacy of IL-12-induced immune stimulation.

In the Brain, Behavior, and Immunity study, Ben Levi and colleagues from Neuroimmunology Research Unit, Tel-Aviv University, Israel, reveal a new mechanism by which stress can affect immunoregulation. They found that exposure to behavioral stress before IL-12 administration diminished the increase in NK number and activity caused by IL-12 in non-stressed animals. This was evident in the marginalizing-pulmonary immune compartment, which is critical for resisting lung metastases.

In addition, in the MADB106 experimental metastases model, the administration of IL-12 efficiently improved MADB106 lung clearance, but continuous stress alongside IL-12 treatment markedly reduced these beneficial effects.

The authors propose that continuous stress affects the ability of IL-12 to cause immunostimulation, irrespective of affecting baseline levels of the measured outcome. According to the authors the neuroendocrine-immune mechanisms behind this phenomenon are yet unknown. It is likely however, that stress may disrupt the efficacy of IL-12 by mounting a Th2 response before the beginning of IL-12 treatment  and thus, consequently hindering the ability of IL-12 to induce an effective Th1 response, which is critical for proper activation of cellular immunity.

In fact, research in the 1990s indicated that mostly systemically, stress hormones cause a selective suppression of Th1 responses and cellular immunity and a Th2 shift towards dominance of humoral immunity.

Thus, this study suggests that systemic elevation of stress hormones may disrupt the efficacy of the immunostimulatory treatment, and these findings may have important clinical implications. For example, patients treated with immunostimulatory agents often experience psychological and physiological stress due to illness and treatment related factors.

Since stress responses in patients may include a continuous systemic elevation of stress hormones that, as shown herein, may disrupt the efficacy of the immunostimulatory treatment, this study may have important clinical implications. Therefore, further insights and studies along these lines may lead to the development of potential interventions that could prevent the disruption to immunostimulatory treatment, and reduce the doses needed and side effects experienced.

SOURCE:  Brain Behav Immun, 2011 25:727. Epub 2011 Jan 28.

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Cover Image Credit: Mechanisms of action of IL12. Different cells derived from myeloid precursors release IL12 upon activation. IL12 induces the release of IFNγ by NK cells, CD4+ T lymphocytes, and CD8+ T lymphocytes. IFNγ is the main mediator of the immunostimulatory properties of IL12 acting on tumor cells, macrophages, lymphocytes, and endothelial cells. From: Revisiting Interleukin-12 as a Cancer Immunotherapy Agent, by Pedro Berraondo, Iñaki Etxeberria, Mariano Ponz-Sarvise and Ignacio Melero; Cancer Res; 24(12); 2716–8. Revisiting Interleukin-12 as a Cancer Immunotherapy Agent | Clinical Cancer Research (aacrjournals.org)

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