A third subunit, the gamma chain, of the human interleukin-2 receptor (IL-2R) was identified, and a complementary DNA clone encoding this member of the cytokine receptor family was isolated. The gamma chain is necessary for the formation of the high- and intermediate-affinity receptors, which consists of alpha beta gamma heterotrimers and beta gamma heterodimers, respectively. The IL-2R on murine fibroblastoid cells can be internalized after binding IL-2 only if the gamma chain is present; alpha and beta are insufficient for internalization. Thus, the gamma chain is an indispensable component of the functional IL-2R.

The p38 mitogen-activated protein kinase (MAPK) is activated in vitro by three different protein kinases: MKK3, MKK4, and MKK6. To examine the relative roles of these protein kinases in the mechanism of p38 MAP kinase activation in vivo, we examined the effect of disruption of the murine Mkk3, Mkk4, and Mkk6 genes on the p38 MAPK signaling pathway. We show that MKK3 and MKK6 are essential for tumor necrosis factor-stimulated p38 MAPK activation. In contrast, ultraviolet radiation-stimulated p38 MAPK activation was mediated by MKK3, MKK4, and MKK6. Loss of p38 MAPK activation in the mutant cells was associated with defects in growth arrest and increased tumorigenesis. These data indicate that p38 MAPK is regulated by the coordinated and selective actions of three different protein kinases in response to cytokines and exposure to environmental stress. Several groups of mitogen-activated protein kinase (MAPK) signal transduction pathways have been identified in mammals, including extracellular signal-regulated protein kinase (ERK), c-Jun NH 2 -terminal kinase (JNK), and p38 MAPK. Each of these groups of MAPK is activated by dual phosphorylation on Thr and Tyr within a tripeptide motif (Thr-Xaa-Tyr) located within the activation loop of the MAPK. This phosphorylation is mediated by seven MAPK kinases (MAPKKs) that have specificity for individual MAPK isoforms. Thus, ERK1 and ERK2 are activated by MEK1 and MEK2, ERK5 is activated by MEK5, JNK is activated by MKK4 and MKK7, and p38 MAPK is activated by MKK3 and MKK6 (Schaeffer and Weber 1999; Kyriakis and Avruch 2001). These MAPKKs and MAPKs can create independent signaling modules that may function in parallel.The mechanism that accounts for the specificity of MAPKKs to activate individual MAPK isoforms is mediated, in part, by an interaction between an N-terminal region located on the MAPKK and a docking site located on the MAPK (Bardwell and Thorner 1996; Enslen and Davis 2001). Recently, structural insight into the mechanism of interaction between a MAPKK and a MAPK has been achieved by X-ray crystallography (Chang et al. 2002). This analysis demonstrated that there is a direct interaction of the N-terminal region of the MAPKK with a docking groove present on the surface of the MAPK distant from the catalytic active site (Weston et al. 2002). A second determinant of MAPKK specificity is the structure of the MAPK activation loop that contains the ThrXaa-Tyr dual phosphorylation motif (Enslen et al. 2000). The specificity of these interactions mediate, in part, the ability of an individual MAPKK to activate a particular MAPK selectively.It is interesting that mammalian MAPK signaling modules include more than one MAPKK because in yeast only a single MAPKK appears to activate each MAPK. The role of this pathway complexity in mammals is unclear. However, it may be significant that individual yeast MAPK isoforms are activated by only a limited group of extracellular stimuli, but mammalian MAPK isoforms are activated by a wide array of extracellular stimuli. It is there...

The gamma chain of the interleukin-2 (IL-2) receptor is an indispensable subunit for IL-2 binding and intracellular signal transduction. A monoclonal antibody to the gamma chain, TUGm2, inhibited IL-2 binding to the functional IL-2 receptors and also inhibited IL-4-induced cell growth and the high-affinity binding of IL-4 to the CTLL-2 mouse T cell line. Another monoclonal antibody, TUGm3, which reacted with the gamma chain cross-linked with IL-2, also immunoprecipitated the gamma chain when cross-linked with IL-4. These results suggest that the IL-2 receptor gamma chain is functionally involved in the IL-4 receptor complex.

This population-based study determined the salivary microbiota composition of 2,343 adult residents of Hisayama town, Japan, using 16S rRNA gene next-generation high-throughput sequencing. Of 550 identified species-level operational taxonomic units (OTUs), 72 were common, in ≥75% of all individuals, as well as in ≥75% of the individuals in the lowest quintile of phylogenetic diversity (PD). These "core" OTUs constituted 90.9 ± 6.1% of each microbiome. The relative abundance profiles of 22 of the core OTUs with mean relative abundances ≥1% were stratified into community type I and community type II by partitioning around medoids clustering. Multiple regression analysis revealed that a lower PD was associated with better conditions for oral health, including a lower plaque index, absence of decayed teeth, less gingival bleeding, shallower periodontal pockets and not smoking, and was also associated with tooth loss. By contrast, multiple Poisson regression analysis demonstrated that community type II, as characterized by a higher ratio of the nine dominant core OTUs, including Neisseria flavescens, was implicated in younger age, lower body mass index, fewer teeth with caries experience, and not smoking. Our large-scale data analyses reveal variation in the salivary microbiome among Japanese adults and oral health-related conditions associated with the salivary microbiome.The human oral cavity is colonized by numerous and diverse microorganisms as commensals. These bacteria constitute complex microbial communities on intraoral surfaces, and dental plaque microbiota that form on the teeth are the cause of two major oral diseases, dental caries and periodontitis. Mutans streptococci are the major etiologic agent of dental caries 1 and Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola are prime suspects in periodontitis 2 . Furthermore, recent studies that have used open-ended molecular approaches and the 16S rRNA gene have implicated other commensal members with the etiology of each disease, such as lactobacilli for dental caries 3 and as many as 17 species, including Filifactor alosis for periodontitis 4 .Saliva is a biological fluid secreted from the salivary glands into the oral cavity and contains bacteria shed from adhering microbial communities on various intraoral surfaces, including tooth surfaces, gingival crevices, tongue dorsum, and buccal mucosa. Oral bacteria in a planktonic state (as in saliva) are not generally regarded as direct causal agents of the oral diseases. However, intraoral transmission of pathogenic bacteria is likely to be mediated by bacteria dispersed via saliva 5,6 .The salivary microbiome, which is comprised of indigenous bacteria that are specific to each person, exhibits long-term stability (on the scale of years) [7][8][9][10] . On the other hand, oral disorders alter the structure of the teeth and their surroundings. Along with the loss of teeth, tooth decay and its treatment alter the structure of the tooth surfaces on which bacteria are attached. Gingival crevi...

Interleukin 2 (IL-2), a T cell-derived cytokine, targets a variety of cells to induce their growth, differentiation, and functional activation. IL-2 inserts signals into the cells through IL-2 receptors expressed on cell surfaces to induce such actions. In humans, the functional IL-2 receptor consists of the subunit complexes of the alpha, beta and gamma chains, or the beta and gamma chains. The third component, the gamma chain, of IL-2 receptor plays a pivotal role in formation of the full-fledged IL-2 receptor, together with the beta chain, the gamma chain participates in increasing the IL-2 binding affinity and intracellular signal transduction. Moreover, the cytokine receptors for at least IL-2, IL-4, IL-7, IL-9, and IL-15 utilize the same gamma chain as an essential subunit. Interestingly, mutations of the gamma chain gene cause human X-linked severe combined immunodeficiency (XSCID) characterized by a complete or profound T cell defect. Among the cytokines sharing the gamma chain, at least IL-7 is essentially involved in early T cell development in the mouse organ culture system. The molecular identification of the gamma chain brought a grasp of the structures and functions of the cytokine receptor and an in-depth understanding of the cause of human XSCID. To investigate the mechanism of XSCID and development of gene therapy for XSCID, knockout mice for the gamma chain gene were produced that showed similar but not exactly the same phenotypes as human XSCID.

Abstract:In this brief review, we discuss our previous research on the relationship between the bacterial composition of salivary microbiota and periodontal disease. Analysis using a terminal restriction fragment length polymorphism method and an international comparison suggest that the predominance of the genera Prevotella and Veillonella in the salivary microbiota is attributable to periodontal disease conditions, and that the predominance of the genus Neisseria indicates healthy periodontal conditions. Furthermore, we recently used next-generation sequencing technology to perform a detailed largescale analysis of the salivary microbiota. An important finding of that study was that high bacterial richness in the salivary microbiota was significantly associated with poor oral health, as indicated by decayed teeth, periodontitis, and poor oral hygiene. Another important result was that relative abundance of predominant bacteria in saliva was significantly associated with oral health-related conditions. Of the two different cohabiting groups of bacteria found in the salivary microbiota, a greater relative abundance of group I bacteria, which include Prevotella and Veillonella species, was associated with poor oral health, high body mass index, and old age. These findings suggest that the salivary microbiota reflects oral and systemic conditions.

We previously reported a new type of signal-transducing adaptor molecule, STAM, which was shown to be involved in cytokine-mediated intracellular signal transduction. In this study, we molecularly cloned a 110-kDa phosphotyrosine protein inducible by stimulation with interleukin 2 (IL-2). The 110-kDa molecule was found to be a human counterpart of mouse Hrs (hepatocyte growth factor-regulated tyrosine kinase substrate) and to be associated with STAM. Tyrosine phosphorylation of Hrs is induced rapidly after stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor as well as hepatocyte growth factor. The mutual association sites of Hrs and STAM include highly conserved coiled-coil sequences, suggesting that their association is mediated by the coiled-coil structures. Exogenous introduction of the wild-type Hrs significantly suppressed DNA synthesis upon stimulation with IL-2 and granulocyte-macrophage colony-stimulating factor, while the Hrs mutant deleted of the STAM-binding site lost such suppressive ability. These results suggest that Hrs counteracts the STAM function which is critical for cell growth signaling mediated by the cytokines.Activation of tyrosine kinases is an initial biochemical event in intracellular signal transduction from cytokine receptors after their bindings with ligands. Although most of the cytokine receptors do not contain any consensus motif of tyrosine kinase, several families of tyrosine kinases, such as the Src family tyrosine kinases, Jak family tyrosine kinases, Syk/ZAP70 family tyrosine kinases, and other family tyrosine kinases (Fes and Tec), are known to be associated with the cytoplasmic domains of cytokine receptors (1). Upon activation of the tyrosine kinases, cytokine receptor subunits are phosphorylated on tyrosine residues, which results in association of the receptor subunits with signal transducers and activators of transcription (Stats) 1 via interaction between the phosphorylated tyrosine residues of receptor subunits and the Src homology 2 (SH2) domains of Stats, and subsequently the Stats are tyrosinephosphorylated by the Jak family tyrosine kinases to be activated as transcription factors (2, 3). For example, interleukin-2 (IL-2) induces activation of Lck (Fyn or Lyn), Syk, and Jak1, all of which are associated with the IL-2 receptor ␤ chain, and Jak3, which is associated with the IL-2 receptor ␥c chain, together with activation of other signaling molecules such as phosphatidylinositol 3-kinase and Shc/Grb2/Sos/Ras/Raf1/mitogen-activated protein kinase cascade (4). Stat5 associated with the IL-2 receptor ␤ chain is activated by Jak3 but not Jak1 upon IL-2 stimulation (5-7). IL-3/granulocyte-macrophage colony-stimulating factor (GM-CSF) also seems to activate Stat5 through Jak2 (8, 9). Activation of Stat5 has been shown to be involved in signaling for DNA synthesis mediated by IL-2 and IL-3 in certain cell lines (10, 11). Jak3 and Jak2 are also known to be essential for induction of c-myc and c-fos upon stimulation with IL-2 and GM-CSF, respective...

The gamma chain of the interleukin-2 (IL-2) receptor is shared with the functional IL-4 receptor and is causatively related to X-linked severe combined immunodeficiency (XSCID), which is ascribed to a profound T cell defect. Studies with monoclonal antibodies specific for the IL-2 receptor gamma chain showed that the gamma chain participates in the functional high-affinity receptor complexes for IL-7 that are involved in the differentiation of T and B cells. Participation of the gamma subunit in more than one receptor may enable the elucidation of the mechanisms of XSCID development and lymphocyte differentiation.