Today, it is known that all human biological functions are under two fundamental regulatory systems, consisting of the endocrine system and the cytokine network. Moreover, it has been shown that the cytokines released from the activated immune cells do not influence only immune functions, but also the whole biological system, including the various metabolic activities, the cardiovascular system, and the functionless of the neuroendocrine system itself. Unfortunately, despite the well-demonstrated importance of cytokines in maintaining the status of health, from a clinical point of view the routine evaluation of the cytokine system still remains unconsidered to establish the status of health, since it is investigated only in severe conditions, such as septic shock, disseminated intravascular coagulation and respiratory distress, which have been demonstrated to be due to an abnormal endogenous production of inflammatory cytokines, namely IL-6, TNF-alpha, and IL-1 beta. This clinical deficiency was depended on several factors, particularly on the complexity of cytokine interactions themselves, but also on the decision to use artificial molecules, such as monoclonal antibodies against the various cytokines, to counteract their eventual abnormally enhanced endogenous production, rather than to investigate the mechanisms responsible for their altered production and to correct eventual alterations. The main reason of the complexity of the cytokine network is related to the fact that the interactions occurring among the different cytokines are often founded on positive feedback mechanisms, then on reciprocal stimulatory actions, while the endocrine system is substantially based on negative feedback circuits. The aim of the present review is to propose a synthetic knowledge regarding the main effects and the source of origin of each single interleukin discovered up to now, to elaborate a first preliminary fundamental physiology of the cytokine network.

The clinical management of patients affected by systemic diseases, including cancer and autoimmune diseases, is generally founded on the evaluation of the only markers related to the single disease rather than the biological immuno-inflammatory response of patients, despite the fundamental role of cytokine network in the pathogenesis of cancer and autoimmunity is well known. Cancer progression has appeared to be associated with a progressive decline in the blood levels of the main antitumor cytokines, including IL-2 and IL-12, in association with an increase in those of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1-beta, and immunosuppressive cytokines, namely TGF-beta and IL-10. On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN-gamma, and IL-18, in association with low levels of TGF-beta and IL-10. However, because of excessive cost and complexity of analyzing the data regarding the secretion of the single cytokines, the relation between lymphocyte-induced immune activation and monocyte-macrophage-mediated immunosuppression has been recently proven to be expressed by the simple lymphocyte-to-monocyte ratio (LMR). The evidence of low LMR values has appeared to correlate with a poor prognosis in cancer and with a disease control in the autoimmune diseases. Moreover, since the in vivo immunoinflammatory response is physiologically under a neuroendocrine modulation, for the evaluation of patient biological response it would be necessary to investigate the function of at least the two main neuroendocrine structures involved in the neuroendocrine modulation of the immune responses, consisting of the hypothalamic-pituitary-adrenal axis and the pineal gland, since the lack of physiological circadian rhythm of cortisol and pineal hormone melatonin has appeared to be associated with a worse prognosis in the human systemic diseases.

The prognosis of the neoplastic diseases depends not only on the biogenetic characteristics of cancer cells but also on the immunological response of patients, which may influence the biological features of cancer cells themselves as well as the angiogenic processes. Moreover, the immune system in vivo is under a physiological psychoneuroendocrine (PNE) regulation, mainly mediated by the brain opioid system and the pineal gland. In more detail, the anticancer immunity is stimulated by the pineal hormone melatonin (MLT) and inhibited by the opioid system, namely, through a mu-opioid receptor. Several alterations involving the pineal endocrine function and the opioid system have been described in cancer patients, which could play a role in tumor progression itself. Therefore, the pharmacological correction of cancer progression-related anomalies could contribute to control cancer diffusion, namely, the pineal endocrine deficiency and the hyperactivity of brain opioid system. In fact, the administration of pharmacological doses of the only MLT has already been proven to prolong the 1-year survival in untreatable metastatic cancer patients. Better results may be achieved by associating other pineal indoles to MLT, mu-opioid antagonists, cannabinoids, beta-carbolines. Moreover, these neuroendocrine combinations may be successfully associated with antitumor cytokines, such as interleukin (IL)-2 and IL-12, as a PNE-immune cancer therapy as well as with antitumor plants as PNE-phytotherapy of cancer in an attempt to propose possible anticancer treatments also to patients with disseminated cancer and untreatable according to the standard oncology.

Background: Despite the negative prognostic significance of lymphocytopenia is known for many years no clinical cancer study has been proposed up to now in an attempt to specifically correct the evidence of an abnormally low lymphocyte count. At present it is known that IL-2 is the main growth factor for T lymphocytes. Lymphocyte proliferation is also stimulated by the pineal indole hormone melatonin (MLT), which is provided by an anticancer activity, whereas it is inhibited by cortisol.Objective: On this basis a preliminary study was carried out to evaluate which may be the optimal therapeutic schedule of cancer-related lymphocytopenia. Methods:The study included 40 advanced solid tumor patients who were treated by the best supportive care (BSC) (n=9), high-dose MLT alone (n=12) at 100 mg/day in the night, subcutaneous low-dose IL-2 alone (n=9) at 1.8 MIU/day for 5 days/week for 2 weeks followed by 2 weeks-rest period, or IL-2 plus MLT. The duration of study was 6 weeks. Results:The results were compared to those found in 10 advanced cancer patients treated by the checkpoint inhibitor Nivolumab (NVB) at 3 mg/kg/b.w. every 15 days. Lymphocyte count rapidly increased in a significant manner on IL-2 therapy, and a greater increase was reached by Il-2 + MLT. Lymphocyte mean count also increased on MLT alone and on NVB, without, however any statistically significant increase. Finally lymphocyte mean count progressively decreased on BSC alone.Conclusions: This preliminary study shows that S.C. low-dose IL-2 is the only drug able to rapidly correct cancer-related lymphocytopenia, whose efficacy may be further amplified by the concomitant endocrine therapy with the pineal hormone MLT. Further studies will be required to evaluate the impact of the lymphocytopenia correction on the survival of advanced cancer patients.

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