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Results for “Paracrine Communication”

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PubMed2000

Strain differences in rabbit adrenocortical structure and morphological evidence of corticomedullary communication.

Interstrain differences in the structure of the mouse and rat adrenal cortex are well known, but related data on rabbits are not available. This study was planned to demonstrate possible strain differences in rabbit adrenal morphology and morphological evidence of a communication between cortex and medulla. For this purpose, the zonation of the adrenal cortex of intact mature male and female rabbits of different strains (New Zealand, Chinchilla and California) were compared using morphometry and the corticomedullary junction was evaluated for close relationship. Marked intersex and interstrain differences were found in the adrenocortical zonation. Female rabbits had larger adrenocortical zones than corresponding males. The rabbits of Chinchilla and California strains had the largest cortical sizes. This difference depended largely upon the higher thickness of the zona fasciculata. Whereas, there were no significant strain differences in the thickness of zona glomerulosa and zona reticularis. Furthermore, examination of corticomedullary junction showed that cortex and medulla were interwoven. Single and small accumulations of cortical cells were spread throughout the medulla. Our morphological data showed the presence of significant interstrain differences in the adrenocortical zonation in the rabbits and provide evidence for a possible paracrine interaction between medullary and cortical cells.

Adrenal Cortex↗
PubMedDate not supplied

Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma.

BACKGROUND: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. METHODS: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. RESULTS: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme - the epithelial mesenchymal trophic unit - leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. CONCLUSIONS: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-betaRs provide targets against which to develop novel therapies for chronic asthma.

Asthma↗
PubMed2003

Glu-Leu-Arg-negative CXC chemokine interferon gamma inducible protein-9 as a mediator of epidermal-dermal communication during wound repair.

Normal wound healing is a complex, highly regulated dynamic process that requires co-ordinate responses of both epidermal and dermal compartments. To accomplish the healing process several growth factors, chemokines, and matrix elements signal both cell proliferation and migration during the inflammatory and reparative phases and limit these responses during the remodeling phase. We have found that the Glu-Leu-Arg-negative CXC chemokines interferon gamma inducible protein 10, monokine induced by interferon gamma, and platelet factor 4, limit fibroblast responsiveness to growth factors, but the functioning of these factors in wound healing remains uncertain. We hypothesized that the keratinocyte-derived member of this Glu-Leu-Arg-negative CXC family, interferon gamma inducible protein 9 (IP-9) CXCL11 (also known as I-TAC, beta-R1, and H-174) signals to the dermal compartment to synchronize the re-epithelialization process. Interferon gamma inducible protein 9 was produced after mechanical wounding of a keratinocyte monolayer, suggesting for the first time that this could be a wound response factor. Interferon gamma inducible protein 9 limited epidermal growth factor (EGF)-induced fibroblast motility (57+/-7%) by the same protein kinase A (KA)-mediated inhibition of calpain activation and cell de-adhesion as described for interferon gamma inducible protein 10. Surprisingly, interferon gamma inducible protein 9 enhanced growth factor-induced motility in undifferentiated keratinocytes (137+/-19%) as determined in a two-dimensional in vitro wound healing assay, and interferon gamma inducible protein 9 alone promoted motility in undifferentiated keratinocytes (49+/-10% of epidermal growth factor-induced motility). A stimulated keratinocyte/target cell coculture system revealed that interferon gamma inducible protein 9 acts as a soluble keratinocyte-derived paracrine factor for both fibroblasts and keratinocytes. Further, we found that in both fibroblasts and undifferentiated keratinocytes, interferon gamma inducible protein 9 exerted its action through modulation of a cytosolic protease, calpain. Interestingly, interferon gamma inducible protein 9 increased calpain activity in undifferentiated keratinocytes, whereas the same chemokine inhibited the calpain activity in fibroblasts. This provides for a model whereby redifferentiated basal keratinocytes could limit fibroblast repopulation of the dermis underlying healed wounds while simultaneously promoting re-epithelialization of the remaining provisional wound.

Calpain↗
PubMed1999

The structure and function of folliculo-stellate cells in the anterior pituitary gland.

The folliculo-stellate cells (FS cells) in the anterior pituitary gland are characterized by their star-like appearance and their ability to form follicles. Although FS cells do not produce any pituitary hormones, their special tendency to surrounding endocrine cells with their long cytoplasmic processes suggests that they regulate endocrine cells by intercellular communication. In spite of many morphological and cytophysiological studies recently performed, a precise understanding of the major functions of FS cells in the pituitary gland remains obscure. We review here the morphological characteristics of FS cells and their suspected functions in the anterior pituitary gland. It is well established that the FS cell produces many kinds of growth factors, i.e., fibroblast growth factor, vascular endothelial cell growth factor and interleukin 6. The biological significances of these growth factors in the anterior pituitary gland are also discussed in this paper. The origin and differentiation of FS cells, especially the possibility that the FS cell is a kind of stem cell which has the potential to differentiate into endocrine cells, is also presented.

Animals↗
PubMed2004

Gap junction-mediated spread of cell injury and death during myocardial ischemia-reperfusion.

Gap junction-mediated intercellular communication (GJMIC) has been known for a long time to be essential in propagation of electrical impulse in the heart, and the contribution of altered GJMIC to the genesis of arrhythmias has been extensively investigated. However, although it is well known that GJMIC allows the exchange of biologically important molecules between adjacent cells, the pathophysiological significance of such chemical coupling during myocardial ischemia and reperfusion is much less known. It has been solidly established that ischemia impairs GJMIC and eventually leads to electrical uncoupling, but recent studies suggest that GJMIC may still allow synchronization of the onset of ischemic rigor contracture and of the progression of ischemic injury beyond rigor onset. During reperfusion, GJMIC has been shown to mediate cell-to-cell propagation of hypercontracture and cell death, and there is evidence that this phenomenon explains the continuity of areas of contraction band necrosis and contributes to final infarct size. Finally, there is increasing evidence that GJ or their protein components are involved in the genesis of the protective effect of ischemic preconditioning, although probably through mechanisms independent from modulator of GJMIC. GJ play an important role in the pathophysiology of cell injury and death during myocardial ischemia-reperfusion and are potential targets for new cardioprotective therapeutic strategies.

Animals↗
PubMed2003

Rat anterior pituitary folliculostellate cells are targets of interleukin-1beta and a major source of intrapituitary follistatin.

Folliculostellate cells of the anterior pituitary are postulated to be an important source of factors, such as follistatin, that regulate pituitary function by intercellular communication. To gain further insight into the function of this cell type, folliculostellate cells were enriched from cultured rat anterior pituitary cells, and an immortalized cell line designated FS/D1h was established and characterized. These FS/D1h cells express S100 immunoreactivity and produce IL-6 but not pituitary hormones such as GH, ACTH, FSH, and LH. Importantly, FS/D1h cells express large amounts of follistatin mRNA and secrete the protein, as quantified indirectly by the amount of [(125)I]activin A immunoprecipitated with a follistatin antiserum. The FS/D1h cells also express alpha, betaA, and betaB inhibin/activin subunit mRNAs, but whether they produce the corresponding activins and inhibins has not been determined. The response of FS/D1h cells to agents thought to modulate folliculostellate cell function was evaluated. IL-1beta (0.005-5 nM) stimulated the secretion of follistatin and increased mRNA expression. In parallel, IL-6 secretion was stimulated. Dexamethasone, pituitary adenylate cyclase-activating polypeptide(1-27), and lipopolysaccharide but not testosterone, 12-O-tetradecanoylphorbol-13-acetate, or forskolin also increased follistatin secretion. Surprisingly, activin had no effect on follistatin mRNA levels, despite the fact that FS/D1h cells express ActRII, ActRIIB, and ALK-4 (ActRIB). Activin, on the other hand, induced Smad7 mRNA accumulation and exerted an antiproliferative effect on FS/D1h cells. Altogether, these observations support the possibility that follistatin originating from folliculostellate cells participates in mediating the effects of IL-1beta, glucocorticoids, and other agents on the response of pituitary cells to activins.

Animals↗
PubMed2004

Pancreatic beta-cells communicate via intermittent release of ATP.

The role of external ATP for intercellular communication was studied in glucose-stimulated pancreatic beta-cells isolated from ob/ob mice. Digital image analyses with fura-2 revealed spontaneous transients of cytoplasmic Ca2+ appearing in synchrony in the absence of cell contacts. After removal of slow oscillations with methoxyverapamil, addition of ATP (0.1-100 microM) resulted in prompt firing of a transient, followed by suppression of the generation and synchronization of spontaneously occurring transients. It was possible to trigger transients during the suppressive phase by raising the concentration of ATP. The dual action of ATP was mimicked by ADP or 2-methylthio-ATP but not by AMP or UTP. The number of spontaneous transients and their synchronization were reduced in the presence of the dephosphorylating agent apyrase. Additional evidence that intermittent release of ATP participates in the generation of spontaneous Ca2+ transients was obtained from the suppression observed from use of antagonists of the purinoceptors [suramin (0.3-30 microM), pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS; 10-30 microM) and 2-deoxy-N-methyladenosine (MRS 2179; 0.3-30 microM)] or from counteracting beta-cell release of ATP by inhibiting exocytosis with 100 nM epinephrine, 100 nM somatostatin, or lowering the temperature below 30 degrees C. The data indicate that ATP has time-dependent actions (prompt stimulation followed by inhibition) on the generation of Ca2+ transients mediated by P2Y receptors. It is proposed that beta-cells both receive a neural ATP signal with coordinating effects on their Ca2+ oscillations and propagate this message to adjacent cells via intermittent release of ATP combined with gap junction coupling.

Action Potentials↗
PubMed2006

Human endothelial cells inhibit BMSC differentiation into mature osteoblasts in vitro by interfering with osterix expression.

It is well accepted, that there is communication between osteoblasts and endothelial cells. However, the influence of endothelial cells on the differentiation of bone precursors into mature osteoblasts is not yet well understood. We therefore studied the effect of human umbilical vein endothelial cells (HUVEC) on human bone marrow stromal cell (BMSC) differentiation towards an osteoblastic phenotype by culturing them in two different types of HUVEC-BMSC cultures (indirect contact, HUVEC-conditioned medium). Typical bone markers (45Ca incorporation, ALP activity, and gene expression of collagen 1 (COL1), osteonectin (ON), matrix metalloproteinase 13 (MMP-13), bone morphogenetic protein 2 (BMP-2)) and transcription factors (Runx2, osterix (OSX)) were evaluated at different time points. The effect of stimulating HUVEC with vascular endothelial growth factor (VEGF) before co-cultures with BMSC was also evaluated. As expected, BMSC in osteogenic medium (OM) (with dexamethasone) differentiated towards the osteoblastic phenotype, as measured by increased matrix mineralization, high ALP activity, and elevated expression of specific osteoblastic marker genes, when compared to BMSC in non-OM. HUVEC reversibly inhibited osteoblastic differentiation of BMSC in OM, independent of the co-culture type. When HUVEC were removed from the cultures, BMSC differentiated into osteoblasts, albeit at a faster rate than BMSC that were never co-cultured with HUVEC. Stimulation of HUVEC with VEGF before co-culture enhanced the inhibitory effect of HUVEC on BMSC differentiation. This inhibitory effect was connected to a reversible suppression of OSX gene expression and was specific to endothelial cells. We conclude that HUVEC can inhibit dexamethasone-induced BMSC differentiation into osteoblasts in vitro, by interfering with OSX expression, thereby arresting BMSC differentiation at a preosteoblastic stage.

Anti-Inflammatory Agents↗
PubMed1999

Correlation of the osteoblastic phenotype with prostate-specific antigen expression in metastatic prostate cancer: implications for paracrine growth.

The characteristic sclerotic appearance of bone metastases from prostate cancer is unexplained but could involve excess peritumoural activity of osteoblast mitogens such as the insulin-like growth factors (IGFs). Since prostatic metastases are distinguished by androgen-dependent secretion of prostate-specific antigen (PSA), a serine protease which cleaves extracellular IGF-binding proteins and thereby enhances the bioavailability of IGFs, the relationship was examined between tumour PSA expression and the osteoblastic phenotype. To this end, a cohort of 27 prostate cancer patients was evaluated to determine the relationship between serum PSA and radiographic bone lesion density at first presentation with metastatic disease. No linear correlation between absolute PSA levels and metastatic osteosclerosis was apparent. However, non-parametric statistical analysis revealed a highly significant link between low-PSA (<20 ng/ml) metastatic prostate cancer and osteolytic bone lesions (p<0.0001, chi(2)=21.5). This finding raises the possibility that the osteoblastic phenotype of prostate cancer derives in part from PSA-dependent proteolysis of IGF-binding proteins within bone matrix.

Bone Neoplasms↗
PubMed2000

Innervation of the gastric mucosa.

A plethora of neuronal messengers ("classical" transmitters, gaseous messengers, amino acid transmitters, and neuropeptides) are capable of mediating or modulating gastric functions. Accordingly, the stomach is richly innervated. Gastric nerves are either intrinsic to the gastric wall, i.e., they have their cell bodies in the intramural ganglia and thus belong to the enteric nervous system, or they reach the stomach from outside, originating in the brainstem, in sympathetic ganglia, or in sensory ganglia. Topographically, the nerve fibers in the stomach reach all layers from the most superficial portions of the gastric glands to the outer smooth muscle layer. This wide distribution implies that virtually all different cell types may be reached by neuronal messengers. Within the gastric mucosa endocrine and paracrine cells (e.g., gastrin cells, ECL cells, somatostatin cells), exocrine cells (parietal cells, chief cells, mucous cells), smooth muscle cells, and stromal cells are regulated by neuronal messengers. The sensory innervation, responding to capsaicin, plays an important role in mucosal protection, and in ulcer healing. Presumably also other nerves are involved and a plasticity in the neuropeptide expression has been demonstrated at the margin of gastric ulcers. Taken together, available data indicate a complex interplay between hormones, paracrine messengers and neuronal messengers, growth factors and cytokines in the regulation of gastric mucosal activities such as secretion, local blood flow, growth, and restitution after damage.

Adrenergic Fibers↗
PubMed1999

Localization of VEGF-B in the mouse embryo suggests a paracrine role of the growth factor in the developing vasculature.

Vascular endothelial growth factor B (VEGF-B) is structurally closely related to VEGF and binds one of its receptors, VEGFR-1. In situ hybridization and immunohistochemistry were used to localize VEGF-B mRNA and protein in embryonic mouse tissues. In 8.5-17.5 day embryos, VEGF-B was most prominently expressed in the developing myocardium, but not in the cardiac cushion tissue. The strong expression in the heart persisted at later developmental stages, while weaker signals were obtained from several other tissues, including developing muscle, bone, pancreas, adrenal gland, and from the smooth muscle cell layer of several larger vessels, but not from endothelial cells. VEGF-B is likely to act in a paracrine fashion, as its receptor is almost exclusively present in endothelial cells. VEGF-B may have a role in vascularization of the heart, skeletal muscles and developing bones, and in paracrine interactions between endothelial and surrounding muscle cells.

Animals↗
PubMed1997

Paracrine interactions between mesothelial and colon-carcinoma cells in a rat model.

This study used a co-culture system with Transwell tissue-culture inserts to investigate the role of primary cultures of rat peritoneal mesothelial cells on the proliferation of rat colon-carcinoma cells (CC531 cells). Mesothelial cells significantly inhibited the growth of CC531 cells, while, conversely, CC531 cells stimulated the growth of mesothelial cells. Receptor-binding studies demonstrated the presence of high-affinity IGF-I receptors on the mesothelial and CC531 cells. Both cell types also produced IGF-I, as measured by radioimmunoassay. IGF-I stimulated DNA synthesis in mesothelial cells, but had no effect on the growth of CC531 cells. In co-culture, it was found that IGF-I potentiated the inhibitory effect of mesothelial cells on CC531 cells. The effect of IGF-I on mesothelial-cell proliferation was additive to the stimulatory effect of CC531 cells. TGF-beta had no effect on the growth of the CC531 cells, suggesting that this growth (-inhibitory) factor is not involved in the inhibitory effect of mesothelial cells on CC531 cell growth. The study provides evidence for the existence of a paracrine loop between mesothelial and colon-carcinoma cells, giving more insight into the basic cellular mechanisms that may modulate the growth of intraperitoneal colon carcinoma. Inhibition of CC531-cell proliferation by rat mesothelial cells might explain the earlier finding that tumour cells grow poorly in a surgically uncompromised abdomen.

Animals↗
PubMed1997

Expression of synaptic membrane proteins in gerbil pinealocytes in primary culture.

Pinealocytes of various mammalian species contain abundant synaptic-like microvesicles (SLMVs) which are considered the endocrine equivalent of neuronal synaptic vesicles. Although the pinealocytes may thus be a suitable cellular model for experimental in vitro studies of SLMVs, nothing is known about the presence of SLMVs in isolated pinealocytes maintained under tissue culture conditions. In the present investigation, we prepared dissociated primary cultures of gerbil pinealocytes to study the expression and distribution of protein components of synaptic vesicles/SLMVs and the presynaptic plasmalemma in pinealocytes kept in vitro. Using immunofluorescence microscopy, we found that cultured pinealocytes readily expressed all synaptic membrane proteins investigated, i.e., synaptophysin, synaptotagmin I, synaptobrevin II, syntaxin I and SNAP-25. Punctuate immunoreactivity for the vesicle-associated proteins could be detected throughout the cell bodies of pinealocytes and was also distributed into all of their processes which began to develop within the first days in culture. Outgrowing processes exhibited growth cone-like structures which were enriched in synaptic vesicle-associated proteins. After 1 week in vitro, pinealocytes had frequently formed an elaborate network of long interwoven processes. Accumulations of synaptic vesicle-associated proteins were observed in varicosities and terminal swellings of the processes. The vesicle-rich process swellings often established synaptic-like process swellings often established synaptic-like contacts with somata and processes of other pinealocytes. Some of the pinealocyte processes possessed additional axon-like properties as demonstrated by their lack of immunoreactivity for the somato-dendritic marker MAP2 and the transferrin receptor. The comparison of the staining patterns for synaptophysin and the endocytotic marker transferrin receptor by confocal laser scanning microscopy revealed a largely differential intracellular distribution of the two proteins. This may indicate that a substantial fraction of pinealocyte SLMVs by-passes the early endosomal-related recycling pathway of SLMVs. Herewith, we have shown that isolated gerbil pinealocytes maintained in primary culture can acquire morphological and neurochemical traits which closely mimick those observed in vivo. In particular, these cultures permit experimental studies of the compartment of pinealocyte SLMVs which seem to make up a major secretory pathway for paracrine intrapineal communication.

Animals↗
PubMed2000

Germ cell suicide: new insights into apoptosis during spermatogenesis.

Mature sperm are the product of a precisely regulated developmental sequence in which germ cell proliferation, differentiation, self-renewal and apoptosis are carefully controlled. The control of germ cell apoptosis during spermatogenesis is especially important. It is mediated by signals derived from the Sertoli cells with which each germ cell is closely associated, as well as by signals originating outside the testis. A greater understanding of these signals is emerging from studies of the spermatogenic defects of genetically modified animals. In particular, the intracellular signaling cascades which ultimately determine germ cell fate are being illuminated by recent studies of the Bcl-2 protein family. This review summarises the crucial role which stringently regulated apoptosis plays in the production of male gametes.

Animals↗
PubMed1999

T cell stimulation upon long-term secretion of viral IL-10.

Viral IL-10 (vIL-10), the IL-10 homologue of Epstein-Barr virus, has so far been described as a cytokine that solely inhibits T cell function. Here we show in vivo and in vitro that after long-term secretion vIL-10 has a stimulatory effect on T cells. For this purpose we employed transfectants derived from a mastocytoma cell line (P815 cells, H-2(d)) constitutively secreting vIL-10 (P815-vIL-10) or expressing the co-stimulatory molecule B7-1 (P815-B7). After in vitro stimulation of splenocytes from syngeneic DBA/2 mice for 7 days in the presence of P815-vIL-10 cells we could detect a marked reduction of proliferation as well as cytotoxicity against P815 target cells. However, this inhibitory effect was reversed when stimulation with P815-vIL-10 cells was extended to 14 days. In vivo P815-vIL-10 cells were rejected whereas P815 cells transfected with a control plasmic were tumorigenic after injection into syngeneic DBA/2 mice. Furthermore, this stimulatory effect of constitutive vIL-10 secretion could be exploited to irradicate already established P815 tumors which were smaller than 5 x 5 mm. In contrast, paracrine vIL-10 secretion for a limited time period of 8 - 9 days was associated with inhibitory effects in vivo: P815-B7 cells, which are normally eliminated in DBA/2 mice, could grow if exposed to temporarily secreted vIL-10. These time-dependent immunomodulatory effects have to be considered in potential therapeutic applications of vIL-10.

Animals↗
PubMed2000

Somatostatin and somatostatin subtype 2A expression in the mammalian retina.

This review discusses the expression and cellular localization of the neuropeptide somatostatin (SRIF) and one of the SRIF subtype (sst) receptors, sst(2A) in the mammalian retina. SRIF immunoreactivity is predominantly localized to a sparse population of amacrine and displaced amacrine cells in the ganglion cell layer in several mammalian retinas including the rat, rabbit, cat, and primate. These cells, characterized by multiple processes, form a sparse network in the inner plexiform layer (IPL) in all retinal regions. Very few processes are also in the outer plexiform layer. In contrast to the predominant distribution of SRIF processes to the IPL, there is a widespread distribution of sst(2A) immunoreactivity to both the inner and outer retina in all mammalian retinas studied to date. In rabbit retina, sst(2A) immunoreactivity is predominant in rod bipolar cells and in sparse wide-field amacrine cells. In the rat retina, sst(2A) immunoreactivity is localized to several neuronal cell types-cone photoreceptors, horizontal cells, rod and cone bipolar cells, and amacrine cells. Reverse-transcriptase-polymerase chain reaction analysis found that sst(2A) mRNA is expressed in the rat retina, while sst(2B) mRNA is not detected. Finally, in the primate retina sst(2) immunoreactivity is predominant in cone photoreceptors, with additional immunostained cell bodies and processes in the inner retina. These findings indicate that SRIF may modulate several neuronal cell types in the retina, and that it has a broad influence on both scotopic and photopic visual pathways.

Animals↗
PubMed2001

Control of T cell hyperactivation in IL-2-deficient mice by CD4(+)CD25(-) and CD4(+)CD25(+) T cells: evidence for two distinct regulatory mechanisms.

In IL-2-deficient mice, antigen-activated CD4 T cells accumulate and cause lethal immune pathology. Wild-type cells of hematopoietic origin present in the same animal are able to prevent this hyperactivation of T cells, but the mechanisms and cells controlling the IL-2-deficient cells are unknown. Here we show that IL-2(-) CD4 cells with an ovalbumin-specific transgenic TCR (IL-2(-) OVAtg) undergo both clonal expansion and clonal contraction when transferred to euthymic recipients and challenged with antigen, but continuously expand in athymic hosts. Cotransfer of wild-type CD4 T cells prevents the accumulation of IL-2-deficient cells. On the residual IL-2(-) TCRtg cells CD69 and CD25 are up-regulated, suggesting that activation per se is not suppressed and that the cells had received an IL-2 signal. Since IL-2 is able to restore the defective antigen-induced cell death (AICD) of IL-2-deficient T cells in vitro, paracrine IL-2 provided by the wild-type CD4 cells may thus be able to allow clonal contraction of IL-2-deficient cells also in vivo. Interestingly however, regulatory CD4(+)CD25(+) cells also efficiently contain the clone size of antigen-stimulated IL-2-deficient T cells. Since CD4(+)CD25(+) cells do not produce IL-2, this suggests a mechanism of suppression distinct from paracrine IL-2 delivery. In keeping with this, the residual IL-2(-) TCRtg cells recovered after cotransfer of regulatory CD4(+)CD25(+) cells do not show increased CD25 or CD69 expression, suggesting that they had not received paracrine IL-2 and that clonal containment occurred at the level of initial activation rather than clonal contraction by AICD. IL-2 deficiency therefore may upset T cell homeostasis by two distinct mechanisms: the failure to program expanding T cells for apoptosis, and the failure to generate functional CD4(+)CD25(+) regulatory cells.

Adoptive Transfer↗
PubMed2006

The interleukin-15/interleukin-15 receptor system as a model for juxtacrine and reverse signaling.

Interleukin-15 (IL-15) is a pleiotropic cytokine of the 4 alpha-helix bundle family, which binds to a receptor complex that displays common elements with the IL-2 receptor and a unique high-affinity alpha chain. This review focuses on juxtacrine and reverse signaling levels in the IL-15/IL-15R system. Specifically, we discuss how agonistic stimulation of membrane-bound IL-15 induces phosphorylation of members of the MAP kinase family and of focal adhesion kinase (FAK), thereby upregulating processes including cytokine secretion, cell adhesion and migration. In addition, we explore IL-15 trans-presentation and intracellular signaling, and define promising molecular targets for future pharmacological intervention in infectious diseases and immunological disorders. These frontiers in IL-15/IL-15Ralpha research serve as highly instructive examples for key concepts, unsolved problems and therapeutic opportunities in juxtacrine and reverse signaling in general.

Animals↗