SummaryInterleukin 5 (I1`5) induces proliferation and differentiation of B cells and eosinophils by interacting with its receptor (I1`5R) which consists of two distinct polypeptide chains, c~ and j8 (~/c). Although both I1`5Ro~ and /3c lack a kinase catalytic domain, I1`5 is capable of inducing tyrosine phosphorylation of cellular proteins. We investigated the role of I1`SKcx in tyrosine phosphorylation of molecules involved in I1`5 signal transduction, using an I1`5-dependent early B cell line, Y16 and transfectants expressing intact or mutant I1`5Rc~ together with intact/3c. The results revealed that the transfectants expressing truncated I1`SKcx, which entirely lacks a cytoplasmic domain, together with/3c, showed neither protein-tyrosine phosphorylation nor proliferation in response to I1`5. This confirms that I1`5Rc~ plays a critical role in protein-tyrosine phosphorylation which triggers cell growth. I1`5 stimulation results in rapid tyrosine phosphorylation of/3c and proteins containing Src homology 2 (SH2) and/or SH3 domains such as phosphatidyl-inositol-3 kinase, Shc, Vav, and HS1, suggesting their involvement in I1`5-mediated signal transduction. IL-5 stimulation significantly enhanced activities of Janus 2 and B cell-specific Bruton's tyrosine kinases (JAK2 and Btk) and increased the tyrosine phosphorylation ofJAK2 kinase. These results and recent data on signaling of growth factors taken together, multiple biochemical pathways driven by tyrosine kinases such as JAK2 and Btk are involved in I1`5 signal transduction.
Systemic sclerosis (SSc)-related autoantibodies are useful tools in identifying clinically homogenous subsets of patients and predicting their prognosis. In this report, we described five SSc patients with anti-centriole antibodies. All five patients were females and had digital ulcers/gangrene. Four of five (80%) patients had pulmonary arterial hypertension (PAH). None of the five patients had active pulmonary fibrosis or developed renal crisis. Anti-centriole antibodies may be a marker for PAH and digital ulcers/gangrene.
Depsipeptide (FK228), a histone deacetylase inhibitor, was recently approved for use in cutaneous T-cell lymphoma. Roxithromycin (RXM) is a macrolide antibiotic that can induce apoptosis of some T-cell lines. In this study, we investigated whether combination of FK228 and RXM had a synergistic inhibitory effect on cell survival of various lymphoma cells and which signaling pathway was affected by the drugs in the presence or absence of chemokines, which were reported to inhibit apoptosis of some tumor cells. FK228 and RXM additively decreased the number of HUT-78, Ki-JK and EL-4 lymphoma cells at doses over 50 nmol/L and 50 lmol/L, respectively. These drugs inhibited phosphorylation of Akt and extracellular signal-regulated kinase (ERK) of EL-4 cells in a dose-dependent manner. Significant association between ERK phosphorylation and cell number or annexin V + cells suggested that the ERK pathway may be critical for survival of EL-4 cells. Combination of 10 or 50 nmol/L of FK228 and 10 lmol/L of RXM decreased cell number of HUT78 and EL-4 compared to a single use of each drug. Our in vitro study suggested that combination of FK228 and RXM may be helpful for enhancing tumor killing effects. Although further study is necessary, this combination may be applicable to patients with cutaneous T-cell lymphoma in the future.
Lymphocyte migration is facilitated by a cascade of adhesion molecule interactions. Specifically, lymphocyte rolling is mediated by selectins, while slow rolling and adhesion are attributed to integrin and Ig family members. α4β7 integrin interactions with its primary ligand, MAdCAM-1, synergize with L-selectin function to regulate the recirculation of naïve lymphocytes to the gut. However, subsets of regulatory T cells also express high levels of L-selectin and α4β7 integrin, and may instead bind to VCAM-1, a secondary ligand for α4β7 integrin. Therefore, potential synergism between L-selectin function and α4β7 integrin/VCAM-1 interactions were examined. To determine the ability of α4β7 integrin to interact with VCAM-1 under conditions of shear, transfected TK-1 T cell interactions with EA.hy926 endothelial cell lines were assessed using an in vitro flow chamber assay. While TK-1 cells, expressing α4β7 but not α4β1 integrin, showed little interaction with VCAM-1-transfected endothelial cells, the presence of L-selectin function enabled α4β7 integrin/VCAM-1 interactions to support slow rolling and adhesion. Importantly, α4β7 integrin interactions with VCAM-1 supported slow rolling and adhesion of murine regulatory T cells under shear stress in the presence of L-selectin function. Thus, functional synergy between L-selectin and α4β7 integrin/VCAM-1 interactions may promote regulatory T cell recruitment to sites of inflammation.
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