Previous studies have shown that malnutrition severely affects both lymphoid and epithelial components of the thymus. Yet, few data are available concerning the extracellular matrix (ECM) of the thymic microenvironment in malnutrition. We studied by histological, ultrastructural, and immunohistochemical means thymuses obtained in necropsies from 19 malnourished children. We observed a consistent increase in the intralobular ECM-containing network which could be ascertained histologically by the dense reticulin staining. This abnormally dense ECM network contained fibronectin, laminin, and type IV collagen. Importantly, the enhancement of thymic ECM in malnourished individuals positively correlated with the degree of thymocyte depletion. This correlation may represent a cause-effect relationship in which the contact of thymocytes with abnormally high amounts of thymic ECM triggers and/or enhances programmed cell death.

BackgroundWe investigated the effects of the signaling molecules, cyclic AMP (cAMP) and protein-kinase C (PKC), on gap junctional intercellular communication (GJIC) between thymic epithelial cells (TEC).ResultsTreatment with 8-Br-cAMP, a cAMP analog; or forskolin, which stimulates cAMP production, resulted in an increase in dye transfer between adjacent TEC, inducing a three-fold enhancement in the mean fluorescence of coupled cells, ascertained by flow cytometry after calcein transfer. These treatments also increased Cx43 mRNA expression, and stimulated Cx43 protein accumulation in regions of intercellular contacts. VIP, adenosine, and epinephrine which may also signal through cyclic nucleotides were tested. The first two molecules did not mimic the effects of 8-Br-cAMP, however epinephrine was able to increase GJIC suggesting that this molecule functions as an endogenous inter-TEC GJIC modulators. Stimulation of PKC by phorbol-myristate-acetate inhibited inter-TEC GJIC. Importantly, both the enhancing and the decreasing effects, respectively induced by cAMP and PKC, were observed in both mouse and human TEC preparations. Lastly, experiments using mouse thymocyte/TEC heterocellular co-cultures suggested that the presence of thymocytes does not affect the degree of inter-TEC GJIC.ConclusionsOverall, our data indicate that cAMP and PKC intracellular pathways are involved in the homeostatic control of the gap junction-mediated communication in the thymic epithelium, exerting respectively a positive and negative role upon cell coupling. This control is phylogenetically conserved in the thymus, since it was seen in both mouse and human TEC preparations. Lastly, our work provides new clues for a better understanding of how the thymic epithelial network can work as a physiological syncytium.