According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells (MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.

The CD18 hypomorphic (CD18^hypo) PL/J mouse model clinically resembling human psoriasis is characterized by reduced expression of the common chain of β₂ integrins (CD11/CD18) to only 2–16% of WT levels. Previously we found that this chronic psoriasiform skin inflammation also depends on the presence of CD4⁺ T cells. Herein we investigated the role of macrophages in this CD18^hypo mouse model. Activated macrophages were significantly increased in lesional skin as well as in inflamed skin draining lymph nodes (DLNs) of affected CD18^hypo mice and were identified as being an important source of TNF-α in vivo. Both depletion of macrophages and neutralization of TNF-α resulted in a significant alleviation of psoriasiform skin inflammation. As monocyte chemotactic protein 1 was enhanced in lesional skin of affected CD18^hypo mice, we intradermally injected recombinant murine monocyte chemotactic protein-1 (rJE/MCP-1) alone or in combination with rTNF-α into the skin of healthy CD18^hypo mice. Only simultaneous injection of rJE/MCP-1 and rTNF-α, but neither substance alone, resulted in the induction of psoriasiform skin inflammation around the injection sites with recruitment and activation of macrophages. Collectively, our data suggest that maintenance of psoriasiform skin inflammation critically depends on efficient recruitment and activation of macrophages with sufficient release of TNF-α.

Background: Morphological and functional changes in the enteric nervous system (ENS) have been reported in inflammatory bowel diseases but it is still uncertain whether neurochemical coding of myenteric neurones is altered in ulcerative colitis (UC). Aims: In this study we investigated transmitter co-localisation in myenteric neurones of normal colon and the colon of patients with UC. Methods: Choline acetyltransferase (ChAT), neurone specific enolase (NSE), vasoactive intestinal peptide (VIP), and substance P (SP) were detected by immunohistochemical methods in whole mounts of colonic myenteric plexus of UC patients (n=10) and controls (n=8). Results: The proportion of ChAT positive and VIP positive neurones relative to the NSE population did not differ in inflamed (33.3% and 9.3%, respectively) and non-inflamed segments (33.6% and 9.7%) of UC colon compared with controls (35.0% and 6.9%). The proportion of SP positive neurones was significantly larger in both inflamed (15.5%) and non-inflamed (20.3%) segments than in controls (5.9%). Analysis of changes in subpopulations showed that 26.9% of neurones were only ChAT positive in controls but that the proportion was significantly smaller in inflamed (18.8%) and non-inflamed (15.8%) areas of UC. The proportions of neurones containing ChAT and SP were significantly higher in inflamed (11.8%) and non-inflamed (13.9%) areas than in controls (5.0%). Conclusion: Remodelling of myenteric neurones in UC involves a shift from mainly cholinergic to more SP positive innervation. This effect may constitute part of the neuronal basis for the motility disturbances observed in UC.

We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte‐adhesion deficiency syndrome‐1 (LAD1) using a murine disease model. In CD18−/− mice, healing of full‐thickness wounds was severely delayed during granulation‐tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers α‐smooth muscle actin and ED‐A fibronectin were substantially reduced in wounds of CD18−/− mice, suggesting an impaired myofibroblast differentiation. TGF‐β signalling was clearly involved since TGF‐β1 and TGF‐β receptor type‐II protein levels were decreased, while TGF‐β1 injections into wound margins fully re‐established wound closure. Since, in CD18−/− mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18−/− neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF‐β1. Indeed, in neutrophil–macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF‐β1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.

The human decidua is a specialized tissue characterized by embryo-receptive properties. It is formed during the secretory phase of menstrual cycle from uterine mucosa termed endometrium. The decidua is composed of glands, immune cells, blood and lymph vessels, and decidual stromal cells (DSCs). In the process of decidualization, which is controlled by oestrogen and progesterone, DSCs acquire specific functions related to recognition, selection, and acceptance of the allogeneic embryo, as well as to development of maternal immune tolerance. In this review we discuss the relationship between the decidualization of DSCs and pathological obstetrical and gynaecological conditions. Moreover, the critical influence of DSCs on local immune cells populations as well as their relationship to the onset and maintenance of immune tolerance is described.

Vav proteins are guanine-nucleotide exchange factors implicated in leukocyte functions by relaying signals from immune response receptors and integrins to Rho-GTPases. We here provide first evidence for a role of Vav3 for β2-integrins–mediated macrophage functions during wound healing. Vav3−/− and Vav1−/−/Vav3−/− mice revealed significantly delayed healing of full-thickness excisional wounds. Furthermore, Vav3−/− bone marrow chimeras showed an identical healing defect, suggesting that Vav3 deficiency in leukocytes, but not in other cells, is causal for the impaired wound healing. Vav3 was required for the phagocytotic cup formation preceding macrophage phagocytosis of apoptotic neutrophils. Immunoprecipitation and confocal microscopy revealed Vav3 activation and colocalization with β2-integrins at the macrophage membrane upon adhesion to ICAM-1. Moreover, local injection of Vav3−/−or β2-integrin(CD18)−/− macrophages into wound margins failed to restore the healing defect of Vav3−/− mice, suggesting Vav3 to control the β2-integrin–dependent formation of a functional phagocytic synapse. Impaired phagocytosis of apoptotic neutrophils by Vav3−/− macrophages was causal for their reduced release of active transforming growth factor (TGF)-β1, for decreased myofibroblasts differentiation and myofibroblast-driven wound contraction. TGF-β1 deficiency in Vav3−/− macrophages was causally responsible for the healing defect, as local injection of either Vav3-competent macrophages or recombinant TGF-β1 into wounds of Vav3−/− mice fully rescued the delayed wound healing.