PubMed · 14901944
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G A von HARNACK. 1951. [Technique and errors in blood count].. https://pubmed.ncbi.nlm.nih.gov/14901944/
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Endocannabinoids are biologically active amides, esters and ether of long chain polyunsaturated fatty acids. They interact with several neurotransmitters in the central nervous system (CNS), and with various signaling molecules (including cytokines) in the periphery. Critical interactions have emerged also with steroids, another group of well-known bioactive lipids, both centrally and peripherally. Here, I briefly review the targets of the combined action of endocannabinoids and steroids, and the available evidence concerning the direct regulation by the latter compounds of the proteins of the endocannabinoid system (ES). In addition, I discuss recent examples of endocannabinoids and steroids working together in the central nervous system and in the periphery, which allowed to disclose some molecular details of the interactions between these two groups of lipids. Taken together, available data suggest that steroids can modulate the endocannabinoid tone, through genomic or nongenomic regulation, and that endocannabinoids can complement the biological activity of steroids. In this line, the issues concerning the tissue- and species-specificity of the endocannabinoid-steroid interface, and the possibility that also endocannabinoids may modulate steroid metabolism, are addressed. Finally, I present the hypothesis that retrograde endocannabinoid signaling, by reducing striatal glutamate release, may be part of the molecular events responsible for the influence of steroids on drug abuse.
CCR7 is necessary to direct dendritic cells (DCs) to secondary lymphoid nodes and to elicit an adaptative immune response. Despite its importance, little is known about the molecular mechanisms used by CCR7 to direct DCs to lymph nodes. In addition to chemotaxis, CCR7 regulates the migratory speed of DCs. We investigated the intracellular pathways that regulate CCR7-dependent chemotaxis and migratory speed. We found that CCR7 induced a G(i)-dependent activation of MAPK members ERK1/2, JNK, and p38, with ERK1/2 and p38 controlling JNK. MAPK members regulated chemotaxis, but not the migratory speed, of DCs. CCR7 induced activation of PI3K/Akt; however, these enzymes did not regulate either chemotaxis or the speed of DCs. CCR7 also induced activation of the GTPase Rho, the tyrosine kinase Pyk2, and inactivation of cofilin. Pyk2 activation was independent of G(i) and Src and was dependent on Rho. Interference with Rho or Pyk2 inhibited cofilin inactivation and the migratory speed of DCs, but did not affect chemotaxis. Interference with Rho/Pyk2/cofilin inhibited DC migratory speed even in the absence of chemokines, suggesting that this module controls the speed of DCs and that CCR7, by activating its components, induces an increase in migratory speed. Therefore, CCR7 activates two independent signaling modules, one involving G(i) and a hierarchy of MAPK family members and another involving Rho/Pyk2/cofilin, which control, respectively, chemotaxis and the migratory speed of DCs. The use of independent signaling modules to control chemotaxis and speed can contribute to regulate the chemotactic effects of CCR7.
Dendritic cells (DCs) are characterized by their unique capacity for primary T cell activation, providing the opportunity for DC-based cancer vaccination protocols. Novel findings reveal that besides their role as potent inducers of tumor-specific T cells, human DCs display additional antitumor effects. Most of these data were obtained with monocyte-derived DCs, whereas studies investigating native blood DCs are limited. In the present study, we analyze the tumoricidal capacity of M-DC8(+) DCs, which represent a major subpopulation of human blood DCs. We demonstrate that IFN-gamma-stimulated M-DC8(+) DCs lyse different tumor cell lines but not normal cells. In addition, we show that tumor cells markedly enhance the production of TNF-alpha by M-DC8(+) DCs via cell-to-cell contact and that this molecule essentially contributes to the killing activity of M-DC8(+) DCs. Furthermore, we illustrate the ability of M-DC8(+) DCs to promote proliferation, IFN-gamma production, and tumor-directed cytotoxicity of NK cells. The M-DC8(+) DC-mediated enhancement of the tumoricidal potential of NK cells is mainly dependent on cell-to-cell contact. These results reveal that, in addition to their crucial role in activating tumor-specific T cells, blood DCs exhibit direct tumor cell killing and enhance the tumoricidal activity of NK cells. These findings point to the pivotal role of DCs in triggering innate and adaptive immune responses against tumors.