Psoriasis is a common chronic skin disease with a largely unknown pathogenesis. We demonstrate here that transgenic over-expression of interleukin (IL)-22 in mice resulted in neonatal mortality and psoriasis-like skin alterations including acanthosis and hypogranularity. This cutaneous phenotype may be caused by the direct influence of IL-22 on keratinocytes, since this cytokine did not affect skin fibroblasts, endothelial cells, melanocytes, or adipocytes. The comparison of cytokines with hypothesized roles in psoriasis pathogenesis determined that neither interferon (IFN)-gamma nor IL-17, but only IL-22 and, with lower potency, IL-20 caused psoriasis-like morphological changes in a three-dimensional human epidermis model. These changes were associated with inhibited keratinocyte terminal differentiation and with STAT3 upregulation. The IL-22 effect on differentiation-regulating genes was STAT3-dependent. In contrast to IL-22 and IL-20, IFN-gamma and IL-17 strongly induced T-cell and neutrophilic granulocyte-attracting chemokines, respectively. Tumor necrosis factor-alpha potently induced diverse chemokines and additionally enhanced the expression of IL-22 receptor pathway elements and amplified some IL-22 effects. This study suggests that different cytokines are players in the psoriasis pathogenesis although only the IL-10 family members IL-22 and IL-20 directly cause the characteristic epidermal alterations.

IntroductionThe immune surveillance of the body is carried out by lymphocytes constantly circulating from the blood to lymphoid or peripheral organs and back to the blood. Most lymphocytes extravasate through specialized vascular endothelium created by tissue microenvironment or inflammation. This suggests that a regional specialization of endothelial cells may control lymphocyte traffic. Postcapillary high endothelial venules (HEVs) are specialized sites along vessels where the migration of lymphocytes to lymphoid organs occurs. 1,2 Migration occurs in a multistep process involving rolling of lymphocytes along the vessel wall, adhesion, and transmigration. 3 The first and the second steps are well described and involve selectins, mucins, immunoglobulin (Ig) superfamily molecules, and integrins. 4,5 The last transmigration step is less well understood and may occur through a transcellular pathway or by the paracellular route. 6 Evidence to support the latter model comes from numerous studies suggesting that the transmigration of leukocytes involves the disruption of interendothelial junctions in a specific and localized manner. [7][8][9] Nevertheless, the molecular events underlying the transmigration process are still controversial because other studies have demonstrated that transendothelial migration may occur without a widespread disruption of tight or adherens junctions. 10,11 In this context, the molecules participating specifically in intercellular junctional complexes of endothelial cells may play a central role in regulating leukocyte transmigration and vascular functions. 12,13 Although all endothelial cells are involved in exchanges of material from blood to tissue, there is a great degree of tissue-specific specialization of vascular junctions. This heterogeneity was described more than 20 years ago when the first electron microscopy studies pointed out structural differences in junctional complexes in different endothelial cells. 14,15 Recently, the molecular characterization of proteins participating in intercellular junctional complexes has increased our understanding of vascular junction heterogeneity. The interendothelial adhesive structures include tight, adherens and gap junctions in which surface proteins such as occludin, claudins, cadherins, or connexins are specifically incorporated. [16][17][18][19] Interestingly, some members of these protein families-among them Claudin-5 and VE-cadherinhave been found to be specifically expressed by endothelial cells. 20,21 Both molecules are involved in vascular integrity and normal vascular function. 22,23 In addition, junctional proteins normally found outside the vascular system may participate to interendothelial junctions of specialized vessels in a tissue-specific manner. This is obvious for occludin, which is highly expressed by the brain vascular bed, but it is barely detectable in other interendothelial junctions. 24 These results led to the concept that the tissue-specific specialization of blood vessels may be mediated by the molecular archi...

The molecular mechanisms underlying lymphocyte extravasation remain poorly characterized. We have recently identified junctional adhesion molecule-2 (JAM-2), and have shown that antibodies to JAM-2 stain high endothelial venules (HEVs) within lymph nodes and Peyer patches of adult mice. Here we show that mouse lymphocytes migrate in greater numbers across monolayers of endothelioma cells transfected with JAM-2. The significance of these findings to an understanding of both normal and pathologic lymphocyte extravasation prompted us to clone the human homologue of JAM-2. We herein demonstrate that an anti-JAM-2 antibody, or a soluble JAM-2 molecule, blocks the transmigration of primary human peripheral blood leukocytes across human umbilical vein endothelial cells expressing endogenous JAM-2. Furthermore, we show that JAM-2 is expressed on HEVs in human tonsil and on a subset of human leukocytes, suggesting that JAM-2 plays a central role in the regulation of transendothelial migration.

We describe here the derivation of a rat monoclonal antibody (mAb) against mouse CD40 (designated 3/23), which stains 45-50% of spleen cells of adult mice, approximately 90% of which are B cells. Interestingly, some 5-10% of both CD4+ and CD8+ T cells in the spleens of (some, but not all) adult, unimmunized mice are also CD40+, whereas CD40+ cells were not detectable in the thymus, even following collagenase digestion. Some 35-40% of lymphoid cells in the bone marrow of adult mice are CD40+ and virtually all of these are B220+, and hence of the B cell lineage: triple-color flow cytometry showed that CD40 is expressed at low levels on some 30% of pre-B cells, at intermediate levels on 80% of immature B cells and on essentially all mature B cells in the bone marrow. These results, therefore, suggest that in the mouse CD40 is expressed relatively late during the process of B cell differentiation. The mAb induced marked up-regulation of major histocompatibility complex class II molecules, CD23 and B7.2 antigens on mature B cells. It also stimulated modest levels of DNA synthesis in mature B cells by itself: this was markedly enhanced by suboptimal concentrations of mitogenic (but not non-mitogenic) anti-mu and anti-delta mAb, and moderately enhanced by co-stimulation with interleukin-4. Hypercross-linking of CD40 (using biotinylated mAb and avidin) also enhanced the proliferative response to anti-CD40.

The ligand for CD40 (CD40L) is a protein which is expressed on CD4 T cells following their activation: CD40-CD40L interactions are absolutely required for the induction of T cell-dependent antibody responses, yet little is known about the mechanisms whereby CD40L+ primary T cells activate naive B cells, since the protein is only transiently expressed and is rapidly down-regulated following T cell-B cell contact. We show here, using a variety of assays, that co-stimulation of primary murine T cells via CD3 and CD28 stabilizes the expression of the CD40L protein. Firstly, T cells stimulated in this manner express higher levels of CD40L when activated in the presence of B cells, compared to CD3-activated T cells. Secondly, the CD40L expressed on CD28-co-stimulated T cells is more resistant to B cell-induced down-regulation. Finally, CD3/CD28-preactivated, rested T cells re-express higher levels of CD40L more rapidly following re-stimulation via CD3 than T cells preactivated via CD3 alone. CD3/CD28-preactivated T cells, but not CD3-activated cells, are competent to induce DNA synthesis in naive B cells, and this requires re-stimulation via CD3 and prolonged ligation of CD40. These data therefore reinforce the concept that naive T cells need to be activated initially by cognate interaction with B7-bearing antigen-presenting cells (such as dendritic cells), before becoming competent helper effector cells capable of driving B cells into proliferation via a CD40-dependent pathway.