'Distant socializing,' not 'social distancing' as a public health strategy for COVID-19.

Social distancing, also referred to as physical distancing, means creating a safe distance of at least two meters (six feet) between yourself and others. This is a term popularized during the COVID-19 pandemic, as it is one of the most important measures to prevent the spread of this virus. However, the term 'social distancing' can be misleading, as it may imply that individuals should stop socializing. However, socializing in a safe context (i.e. over the phone, video-chat, etc.) is especially important during this time of crisis. Therefore, in this narrative review, we suggest the term 'distant socializing' as more apt expression, to promote physical distancing measures while also highlighting the importance of maintaining social bonds. Further, articles discussing the practice, implementation, measurement, and mental health effects of physical distancing are reviewed. Physical distancing is associated with psychiatric symptoms (such as anxiety and depression), suicidal ideation, and domestic violence. Further, unemployment and job insecurity have significantly increased during COVID-19, which may exacerbate these negative mental health effects. Governments, medical institutions, and public health bodies should therefore consider increasing mental health resources both during and after the pandemic, with a specific focus on frontline workers, COVID-19 survivors, and marginalized communities.

Melatonin: Nature's most versatile biological signal?

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.

Colony-stimulating activity and hematopoietic rescue from cancer chemotherapy compounds are induced by melatonin via endogenous interleukin 4.

We have reported that melatonin may rescue bone marrow cells from apoptosis induced either in vivo or in vitro by cancer chemotherapy compounds via bone marrow T-cells and endogenous release of granulocyte-macrophage colony-stimulating factor. Here we show that the number of granulocyte/macrophage colony-forming units cultured with suboptimal concentrations of colony-stimulating factor was higher in the presence of melatonin both at physiological and pharmacological concentrations. CD4+,Thy-1.2+ cell depletion or addition of anti-mouse interleukin 4 monoclonal antibodies prevented both effects of melatonin. Upon incubation with etoposide, the concentration of myeloid precursors was 43 +/- 8 per 10(5) cells. The melatonin+etoposide value was 68 +/- 7, whereas that of melatonin+etoposide+anti-interleukin 4 was 38 +/- 6. Melatonin was also ineffective when bone marrow cells were separated in adherent and nonadherent populations. Supernatants from nonadherent cells incubated with melatonin proved to contain interleukin 4 activity which, however, showed its influence on unseparated bone marrow and adherent cells but not on nonadherent cells. It is proposed that melatonin represents a neuroendocrine regulator of interleukin 4 production in bone marrow T-helper cells. Interleukin 4 may then stimulate adherent stromal cells to produce granulocyte/macrophage colony-stimulating factor. Such a neuroendocrine-cytokine mechanism may explain the hematopoietic rescue of melatonin as well as its antitumoral and immunoenhancing properties.

Hematopoietic rescue via T-cell-dependent, endogenous granulocyte-macrophage colony-stimulating factor induced by the pineal neurohormone melatonin in tumor-bearing mice.

We investigated whether melatonin can affect tumor growth and/or hematopoiesis in mice transplanted with Lewis lung carcinoma and treated with cyclophosphamide or etoposide. These agents were injected i.p. for 5 days at two different cumulative doses (cyclophosphamide, 40 and 160 mg/kg body weight; etoposide, 20 and 40 mg/kg body weight) from day 8 through day 12 after tumor transplantation. Melatonin was injected s.c. at a dose of 1 mg/kg body weight/day, from day 8 throughout the experiments and from days 8 through 12 or from day 13 onwards. Melatonin did not influence tumor growth but selectively counteracted bone marrow toxicity when administered together with the cancer chemotherapy compounds without interfering with their anticancer action. In vitro, melatonin proved to counteract apoptosis in bone marrow cells incubated with etoposide. Such protection was reflected by an increased frequency of granulocyte/macrophage-colony forming units but not of the pluripotent spleen-colony forming units. The effect of melatonin was neutralized by anti-granulocyte/macrophage-colony-stimulating factor monoclonal antibodies. When athymic, T-cell-deficient mice were used as bone marrow donors, melatonin did not exert any protective effect. This suggested that melatonin is able to stimulate the endogenous production of granulocyte/macrophage-colony-stimulating factor via bone marrow T-cells. Due to the well known lack of toxic and undesirable side effects of melatonin, these findings might have a straightforward clinical application.

Melatonin in relation to the antioxidative defense and immune systems: possible implications for cell and organ transplantation.

Melatonin, a molecule synthesized and secreted by the mammalian (including human) pineal gland, has a variety of seemingly unrelated functions in organisms. In photoperiodically-dependent seasonal breeders, the changing melatonin signal imparts seasonal information to the species thereby regulating the annual cycle of reproduction Melatonin also is involved in a number of 24 h rhythms and is believed to be an important component of the circadian system. More recently, melatonin was found to relate to immune function in organisms and to be an effective antioxidant. As an antioxidant melatonin would appear to provide substantial protection against free radicals which are generated under a variety of experimental corrections, including ischemia/reperfusion injury. These latter two functions of melatonin, i.e., as an immune system modulator and as an antioxidant, both may have applicability to cell and organ transplantation.

Melatonin, immune function and aging.

Aging is associated with a decline in immune function (immunosenescence), a situation known to correlate with increased incidence of cancer, infectious and degenerative diseases. Innate, cellular and humoral immunity all exhibit increased deterioration with age. A decrease in functional competence of individual natural killer (NK) cells is found with advancing age. Macrophages and granulocytes show functional decline in aging as evidenced by their diminished phagocytic activity and impairment of superoxide generation. There is also marked shift in cytokine profile as age advances, e.g., CD3+ and CD4+ cells decline in number whereas CD8+ cells increase in elderly individuals. A decline in organ specific antibodies occurs causing reduced humoral responsiveness. Circulating melatonin decreases with age and in recent years much interest has been focused on its immunomodulatory effect. Melatonin stimulates the production of progenitor cells for granulocytes-macrophages. It also stimulates the production of NK cells and CD4+ cells and inhibits CD8+ cells. The production and release of various cytokines from NK cells and T-helper lymphocytes also are enhanced by melatonin. Melatonin presumably regulates immune function by acting on the immune-opioid network, by affecting G protein-cAMP signal pathway and by regulating intracellular glutathione levels. Melatonin has the potential therapeutic value to enhance immune function in aged individuals and in patients in an immunocompromised state.

Modulation of hematopoiesis via alpha 1-adrenergic receptors on bone marrow cells.

We have recently demonstrated that adrenergic agents can affect hematopoiesis after syngeneic bone marrow transplantation in mice. In particular, chemical sympathectomy by 6-hydroxydopamine (6-OHDA) and/or administration of the alpha 1-adrenergic antagonist prazosin were shown to increase the concentration of blood granulocytes, platelets, and bone marrow colony-forming units-granulocyte/macrophage (CFU-GM), and to induce a granulocytic hyperplasia of the spleen. Here we show that prazosin can also enhance myelopoiesis and platelet formation in normal mice. Furthermore, noradrenaline and the alpha 1-adrenergic agonist methoxamine could directly inhibit the in vitro growth of GM-CFU. The effect of noradrenaline was counteracted by prazosin and by other alpha-adrenergic antagonists such as phentolamine and yohimbine, in the following order of potency: prazosin > phentolamine > yohimbine. In line with these results, we were able to demonstrate that 3H-prazosin binds specifically to both bone marrow cell membranes and intact bone marrow cells. Scatchard analysis of the binding to intact cells revealed the presence of two binding sites. A kd of 0.98 +/- 0.32 nM and a B max of 5 +/- 2.9 fM/2 x 10(6) cells characterized the higher affinity site, while the lower affinity site displayed a kd of 55.9 +/- 8.2 nM and a B max of 44 +/- 7.7 fM/mg protein. These saturation studies, together with competition experiments to evaluate the ability of various adrenergic compounds to displace 3H-prazosin binding, classified the higher affinity site as an alpha 1-adrenergic receptor. The remaining low affinity binding site remains to be characterized. Furthermore, separation of bone marrow cells by counterflow centrifugal elutriation (CCE) showed that the high-affinity binding is due to a lymphoid/stem cell fraction with no blasts and no GM-CFU progenitors. The low-affinity site was apparent on the rotor-off fraction, which was enriched with GM-CFU progenitor cells. These findings demonstrate that alpha-adrenergic receptors are present on bone marrow cells and participate in the regulation of hematopoiesis.

Norepinephrine protects mice from acute lethal doses of carboplatin.

We demonstrated in previous studies that adrenergic agents may affect hematopoiesis via high- and low-affinity alpha1-adrenoceptors present on bone marrow (BM) cells [1-3]. Here we show that norepinephrine administration in mice rescued hematopoiesis from the toxic effect of the non-cell cycle specific chemotherapeutic agent, carboplatin. Protection of granulocyte/macrophage colony-forming units (GM-CFUs) was already apparent only a few hours after carboplatin and norepinephrine administration. On day 3, hematopoietic rescue was reflected by higher leukocyte and platelet counts. At its most effective dose (3 mg/kg, subcutaneously injected), norepinephrine protected 77% of the mice previously injected intravenously with 200 mg/kg of carboplatin (LD 100: 170 mg/kg). Simultaneous administration of the alpha1-adrenoceptor antagonist prazosin reduced the percentage of surviving mice to 30%, indicating that alpha1-adrenoceptors mediated most of the norepinephrine-induced hematopoietic rescue. Consistently, prazosin administration also reduced blood counts and GM-CFUs. In vitro, norepinephrine (1 microM) rescued GM-CFUs in BM cells, although this effect was counteracted by low concentrations (0.1-10 nM) of prazosin. Our findings indicate a previously undescribed novel mechanism of hematopoietic regulation and may find application in preventing the myeloablative effect of anticancer treatments.

Neural and endogenous catecholamines in the bone marrow. Circadian association of norepinephrine with hematopoiesis?

Members of our research team have recently reported that adrenergic agents may affect hematopoiesis via alpha1-adrenoceptors present on bone marrow B cell precursors. In this paper we demonstrate that murine bone marrow contains a substantial amount of catecholamines. Norepinephrine (NE) and dopamine (DA) exhibited a daily rhythmicity, with peak values observed during the night. The rhythm was disrupted by chemical sympathectomy, whereas epinephrine (E) showed no rhythmicity or sensitivity to 6-hydroxydopamine. High and low values of NE and DA were associated with high and low values of their metabolites, which indicated a rhythmic catecholamine release. NE, but not DA or E, was positively associated with the proportion of cells in the G2/M and S phases of the cell cycle. Moreover, NE and DA were found in both short-term and long-term bone marrow cultures as well as in human or murine B lymphoid cell lines. These findings indicate that endogenous catecholamines in the bone marrow have both neural and cellular origins. The neural input shows a daily rhythm and may be implicated in the regulation of hematopoiesis.

The biological significance of soluble interleukin-2 receptors in solid tumors.

In an attempt to further understand the biological significance of soluble IL-2 receptors (sIL-2R) in solid tumors, we have evaluated 160 cancer patients (breast: 40; lung: 66; colon: 18; stomach: 22; uterine cervix: 14) and 58 healthy subjects, as controls. Serum mean levels of sIL-2R, measured with an enzyme immunoassay, were significantly higher in cancer patients than in controls. Metastatic cancer patients showed significantly higher values than the non-metastatic ones; this difference was significant in all tumor histotypes, except small cell lung carcinoma. Moreover, in 15 patients in whom sIL-2R were evaluated either before or after radical surgery, a significant surgery-induced increase in sIL-R mean values was seen. Finally, the chemotherapy-induced rise in sIL-2R appeared to be associated with a lack of clinical response. These results seem to suggest that sIL-2R may be a marker of host biological response in patients with solid tumors, the significance of which needs further investigation.

Neuroimmunotherapy of advanced solid neoplasms with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: preliminary results.

On the basis of the demonstrated existence of immunoneuroendocrine interactions and on the previously observed synergistic action between the pineal hormone melatonin (MLT) and interleukin-2 (IL-2), we have designed a neuroimmunotherapeutic combination consisting of low-dose IL-2 and MLT in the treatment of advanced solid neoplasms. The study included 24 patients with advanced solid tumours (non-small cell lung cancer 9; colorectal cancer 7; gastric cancer 3; breast cancer 2; cancer of pancreas 1; hepatocarcinoma 1; unknown primary tumour 1), 21 of whom showed distant organ metastases. Not all patients responded to previous chemotherapies, or had tumours for which no standard therapy was available. Moreover, not all patients were able to tolerate IL-2 immunotherapy at the conventional doses. IL-2 was given subcutaneously at a dose of 3 x 10(6) U/day at 8:00 p.m. for 6 days/week for 4 weeks. MLT was given orally at a dose of 50 mg at 8:00 p.m. every day, starting 7 days before IL-2 injection. In non-progressed patients, a second cycle was given after a 21-day rest period. A partial response was seen in 3/24 patients (lung 2; stomach 1; duration: 11, 4, 4 months, respectively). Moreover, a minimal response (duration: 8+ months) was seen in 1 lung cancer patient. Stable disease was obtained in 14/24 patients (median duration: 6+ months), while the remaining 6 patients progressed. An improvement in performance status was seen in 7/24 patients. No important toxicity was observed. Mean eosinophil and lymphocyte levels significantly increased during the immunotherapy, and their rise was significantly higher in patients with response or stable disease than in those with progressive disease. These preliminary results show that neuroimmunotherapy with low-dose IL-2 and the pineal hormone MLT is a biologically active and well tolerated strategy, capable of determining an apparent control of tumour growth in patients with advanced solid neoplasms, for whom no standard effective therapy is available.

Low-dose interleukin-2 subcutaneous immunotherapy in association with the pineal hormone melatonin as a first-line therapy in locally advanced or metastatic hepatocellular carcinoma.

Experimental studies have showed that hepatocellular carcinoma (HCC) cells are susceptible to cytolysis of interleukin (IL)-2-activated lymphocytes. Moreover, our previous studies demonstrated that the pineal neurohormone melatonin (MLT) may enhance IL-2 efficacy. On this basis, a study was started with low-dose IL-2 (3 million U/day subcutaneously for 6 days/week for 4 weeks) plus MLT (50 mg/day orally every day given in the evening) as a first-line therapy of unresectable HCC. The study included 14 patients. Objective tumour regressions were obtained in 5/14 (36%) patients (one complete response, four partial responses), with a median duration of 7+ months. 6 patients had stable disease, while the other 3 progressed. Toxicity was low in all cases. This study shows that the neuroimmunotherapy with low-dose IL-2 plus MLT is a new well-tolerated and effective therapy of advanced HCC.

The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties.

In previous studies we showed that in mice the pineal gland modulates the immune response via the circadian synthesis and release of melatonin. Exogenous melatonin proved also to exert immunoenhancing effects and to counteract completely the immunologic effect of acute stress. Melatonin was active only in vivo, in mice primed with T-dependent antigens and its effects on the primary antibody response and thymus weight were abolished by the specific opioid antagonist naltrexone. Here we demonstrate that physiologic concentrations of melatonin stimulate, in vitro, activated L3T4+ (CD4+) cells to release opioid agonist(s) that can reproduce in vivo the immunoenhancing and anti-stress effects on thymus cellularity and antibody production of melatonin and compete with specific binding of [3H]naloxone to mouse brain membranes. Similar results were obtained when mitogen-activated human immunocompetent cells were incubated with melatonin. In the human model the results were, however, less consistent than those obtained with murine cells, in that only four out of ten blood donors provided cells that were responsive to melatonin. This finding elucidates the mechanism of a novel immuno-neuroendocrine connection with relevant implications for our understanding of the neuroendocrine factors that may influence the immune response in vivo in normal and stressful situations. In addition, it opens new perspectives in a wide range of research fields.

Role of the pineal gland in immunity. Circadian synthesis and release of melatonin modulates the antibody response and antagonizes the immunosuppressive effect of corticosterone.

Inhibition of synthesis of the pineal neurohormone melatonin (MEL) in mice, by administration of propranolol (PRO) in the evening, and daily injections of p-chlorophenylalanine (PCPA), resulted in a significant depression of the primary antibody response to sheep red blood cells (SRBC). Spleen cells from these mice showed a reduced reactivity against antigens in the autologous mixed lymphocyte reaction (AMLR). In contrast, alloreactivity remained normal. Reconstitution of the night-time peak of plasma MEL by evening injections to the mice completely reversed the suppression of the humoral response and the AMLR. MEL administration was able to antagonize the depression of antibody production induced by corticosterone in vivo. These results suggest that the pineal gland has important immunomodulatory functions through its cyclic, circadian release of MEL.

Dominance and persistence of donor marrow in long-lived allogeneic radiation chimeras obtained with unmanipulated bone marrow.

Allogeneic, H-2-incompatible irradiation chimeras (H-2d leads to H-2b) constructed with normal, unmanipulated bone marrow and with marrow-derived factors live long and do not manifest a GvH disease. Their response to primary immunization is deficient but their alloreactivity is normal. This chimeric allotolerance cannot be passively transferred from chimeric donors to normal irradiated recipients. Passive transfer of both donor- or recipient-type immunocompetent T-cells into the chimeric mice does not lead to syngeneic reconstitution, rejection of the engrafted marrow or GvH disease and the mice maintain permanently their chimerism. This new model demonstrates that chimerism is not eradicable in long-lived chimeras reconstituted with unmanipulated bone marrow, and that the bone marrow itself plays a dominant role in maintenance of chimerism.

Melatonin: a principal neuroimmunoregulatory and anti-stress hormone: its anti-aging effects.

Major environmental variables such as daily and seasonal changes of light and temperature regulate the daily circadian variations of synthesis and release of the pineal neurohormone N-acetyl-5-methoxytryptamine (melatonin). Melatonin has now been shown to be a potent immunoregulatory agent, and to be able to antagonize the immunosuppressive effects of acute anxiety stress in mice, as measured by antibody production, by thymus weight, and by the capacity of stressed- and evening-melatonin-treated mice to react against a lethal virus. Both psychogenic factors and infectious agents such as viruses can act as "stressors" and induce an immunosuppression. Their combination is a determinant for the course of infectious diseases and, perhaps, cancer. Circadian (evening) melatonin possesses thus the singular ability to up-regulate the immunosuppression of stressed mice. This effect of melatonin is not exerted directly on immunocompetent cells, but mediated via the endogenous opioid system upon antigen-activation of T cells. Melatonin being a short-lived hormone with negligible side-effects which is rapidly degraded and eliminated by the body, the use of melatonin offers a new approach to the physiological control of stress and stress-related infectious diseases. In addition, melatonin could be used for the potentiation of primary immunization (vaccination) against antigens of the most varied nature which do not evoke a robust or longlasting secondary (memory) response. The regulatory function of pineal melatonin is discussed also in relation to hematopoiesis, to its oncostatic effects, and to its possible dual role in reproduction physiology and generation of immunocompetence and tolerance during ontogeny.

The immunotherapeutic potential of melatonin.

The interaction between the brain and the immune system is essential for the adaptive response of an organism against environmental challenges. In this context, the pineal neurohormone melatonin (MEL) plays an important role. T-helper cells express G-protein coupled cell membrane MEL receptors and, perhaps, MEL nuclear receptors. Activation of MEL receptors enhances the release of T-helper cell Type 1 (Th1) cytokines, such as gamma-interferon (gamma-IFN) and IL-2, as well as of novel opioid cytokines. MEL has been reported also to enhance the production of IL-1, IL-6 and IL-12 in human monocytes. These mediators may counteract stress-induced immunodepression and other secondary immunodeficiencies and protect mice against lethal viral encephalitis, bacterial diseases and septic shock. Therefore, MEL has interesting immunotherapeutic potential in both viral and bacterial infections. MEL may also influence haemopoiesis either by stimulating haemopoietic cytokines, including opioids, or by directly affecting specific progenitor cells such as pre-B cells, monocytes and NK cells. MEL may thus be used to stimulate the immune response during viral and bacterial infections as well as to strengthen the immune reactivity as a prophylactic procedure. In both mice and cancer patients, the haemopoietic effect of MEL may diminish the toxicity associated with common chemotherapeutic protocols. Through its pro-inflammatory action, MEL may play an adverse role in autoimmune diseases. Rheumatoid arthritis patients have increased nocturnal plasma levels of MEL and their synovial macrophages respond to MEL with an increased production of IL-12 and nitric oxide (NO). In these patients, inhibition of MEL synthesis or use of MEL antagonists might have a therapeutic effect. In other diseases such as multiple sclerosis the role of MEL is controversial. However, the correct therapeutic use of MEL or MEL antagonists should be based on a complete understanding of their mechanism of action. It is not yet clear whether MEL acts only on Th1 cells or also on T-helper Type 2 cells (Th2). This is an important point as the Th1/Th2 balance is of crucial importance in the immune system homeostasis. Furthermore, MEL being the endocrine messenger of darkness, its endogenous synthesis depends on the photoperiod and shows seasonal variations. Similarly, the pharmacological effects of MEL might also be season-dependent. No information is available concerning this point. Therefore, studies are needed to investigate whether the immunotherapeutic effect of MEL changes with the alternating seasons.

Allogeneic H-2d leads to H-2b irradiation bone marrow chimeras: a) failure to transfer chimerism adoptively and b) immune reactivity of immunocompetent lymphocytes adoptively transferred to chimeras.

Long-lived, GVHD-free, H-2 incompatible haemopoietic chimeras (P1 leads to P2) were constructed transfusing unmanipulated bone marrow cells together with recently identified marrow-regulating factors (MRF) in lethally irradiated recipients. The chimeric tolerance of P1 leads to P2 chimeras proved to be adoptively untransferable. Another peculiar property of established P1 leads to P2 allochimeras was their ability to "suppress" or reject passively transfused immunocompetent P1 or P2 lymphocytes. Even this "suppression" appeared to be untransferable and to operate in the chimera only in a fashion dependent upon the age of the established chimeras. This chimeric "unidentified suppressive principle" seems not to follow familiar immunologic lines. A relationship with the mechanism of chimeric tolerance is suggested.

Is hematopoiesis under the influence of neural and neuroendocrine mechanisms?

It is well recognized that the immune response is under the influence of a variety of neural or neuroendocrine mechanisms. Much less studied is the possible influence of these mechanisms on hematopoiesis. Here I review the existing evidence about a neural and/or neuroendocrine regulation of hematopoiesis. The physiology of the blood forming system seems to be controlled at three levels, i.e. at the cellular level by the bone marrow stroma, at the humoral level by hematopoietic cytokines and finally by catecholamines and neuroendocrine factors. Bone marrow catecholamines originate from sympathetic nerve fibers and from hematopoietic cells directly. Catecholamines of neural origin show a circadian rhythmicity. Adrenoceptors present on bone marrow cells include the alpha 1-subtype which seems to mediate the catecholaminergic control of hematopoiesis. Neuroendocrine factors including substance P, neurokinin-A and the pineal hormone melatonin might also influence hematopoiesis by affecting hematopoietic cytokines. In particular, melatonin seems to affect hematopoiesis via the induction in bone marrow T-helper cells of two novel opioid cytokines. A complete understanding of the neural and neuroendocrine regulation of hematopoiesis might provide new conceptual and therapeutic perspectives in a variety of hematopoietic and immune diseases.

Neurohormones and catecholamines as functional components of the bone marrow microenvironment.

A variety of cytokines and growth factors exert a finely tuned control on the complex series of proliferative and differentiative events called hematopoiesis. Recent studies have shown that neuroendocrine and neural factors may also regulate hematopoiesis. In particular, besides its important immunoenhancing properties, the pineal neurohormone melatonin can also rescue hematopoiesis from the toxic effect of anti-cancer drugs via the action of T-helper cell novel opioid cytokines. In turn, these substances bind kappa-opioid receptors expressed in GM-CSF-activated macrophage-like stromal cells and seem to stimulate IL-1. Adrenergic agents can also affect hematopoiesis. We demonstrated that pre-B cells express alpha 1B-adrenoceptors (alpha 1B-AR) and that their activation by catecholamines results in suppressed myelopoiesis in vitro or protection in vivo against supralethal doses of carboplatin. Most recently, we found that alpha 1B-AR gene knockout mice show a deranged hematopoietic recovery after sublethal irradiation. Regeneration of pre-B cells (the cell type expressing alpha 1B-AR) and of erythrocytes was much faster in knockout than in wild-type mice. Most interesting, bone marrow cells can synthesize both melatonin and catecholamines. As far as melatonin is concerned, human and murine bone marrow cells contain and synthesize melatonin at a concentration that is three orders of magnitude higher than that normally found in serum. Catecholamines are also present in substantial amounts and originate both from nerve endings and bone marrow cells. These findings open interesting new perspectives and include hematology among the disciplines that would benefit from the integrative NIM approach.