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Liver parenchyma heterogeneity in the response to extracellular NAD+.

The perfused rat liver responds intensely to NAD+ infusion (20-100 microM). Increases in portal perfusion pressure and glycogenolysis and transient inhibition of oxygen consumption are some of the effects that were observed. The aim of the present work was to investigate the distribution of the response to extracellular NAD+ along the hepatic acinus. The bivascularly perfused rat liver was used. Various combinations of perfusion directions (antegrade and retrograde) and infusion routes (portal vein, hepatic vein and hepatic artery) were used in order to supply NAD+ to different regions of the liver parenchyma, also taking advantage of the fact that its extracellular transformation generates steep concentration gradients. Oxygen uptake was stimulated by NAD+ in retrograde perfusion (irrespective of the infusion route) and transiently inhibited in antegrade perfusion. This indicates that the signal causing oxygen uptake inhibition is generated in the periportal area. The signal responsible for oxygen uptake stimulation is homogenously distributed. Stimulation of glucose release was more intense when NAD+ was infused into the portal vein or into the hepatic artery, indicating that stimulation of glycogenolysis predominates in the periportal area. The increases in perfusion pressure were more pronounced when the periportal area was supplied with NAD+ suggesting that the vasoconstrictive elements responding to NAD+ predominate in this region. The response to extracellular NAD+ is thus unequally distributed in the liver. As a paracrine agent, NAD+ is likely to be released locally. It can be concluded that its effects will be different depending on the area where it is released.

Animals↗
PubMed2006

Localization of soluble guanylyl cyclase in the superficial dorsal horn.

Nitric oxide (NO) has been implicated in pain processing at the spinal level, but the mechanisms mediating its effects remain unclear. In the present work, we studied the organization of the major downstream effector of NO, soluble guanylyl cyclase (sGC), in the superficial dorsal horn of rat. Almost all neurokinin 1 (NK1) receptor-positive neurons in lamina I (a major source of ascending projections) were strongly immunopositive for sGC. Many local circuit neurons in laminae I-II also stained for sGC, but less intensely. Numerous fibers, presumably of unmyelinated primary afferent (C fiber) origin, stained for calcitonin gene-related peptide or isolectin B4, but none of these was immunopositive for sGC. These data, along with immunoelectron microscopy results, imply that unmyelinated primary afferent fibers terminating in the superficial dorsal horn lack sGC. Double labeling showed that neuronal nitric oxide synthase (nNOS) seldom colocalized with sGC, but nNOS-positive structures were frequently closely apposed to sGC-positive structures, suggesting that in the superficial dorsal horn NO acts mainly in a paracrine manner. Our data suggest that the NK1 receptor-positive projection neurons in lamina I are a major target of NO released in superficial dorsal horn. NO may also influence local circuit neurons, but it does not act on unmyelinated primary afferent terminals via sGC.

Afferent Pathways↗
PubMed2003

Thyroid transcription factor (TTF) -1 regulates the expression of midkine (MK) during lung morphogenesis.

Midkine (MK) is a 13-kDa heparin-binding growth factor that is thought to mediate developmental processes, including vasculogenesis, cell migration, and proliferation in various organs. To determine whether MK plays a role during lung morphogenesis, immunostaining for MK was assessed in mouse lung from embryonic day (E) 13 to postnatal day (PN) 24. MK was detected in mesenchymal and respiratory epithelial cells of the peripheral mouse lung from E13.0 to E15.5. From E18.5 to PN1, MK was observed primarily in epithelial cells lining conducting airways and peripheral lung saccules. By PN10, expression was no longer observed in respiratory epithelial cells but was readily detected in small blood vessels in the alveolar region of the lung. Although most respiratory epithelial cells uniformly expressed MK before E13.0, MK was restricted to subsets of cells by E18.5, colocalizing with the Clara cell secretory protein (CCSP) marker in conducting airways and with pro-SPC, a marker specific for alveolar type II pneumocytes. By PN10, MK was not detected in respiratory epithelial cells of the conducting airways and was closely associated with capillary networks. The sites of intense MK staining in the respiratory epithelial cells correlated with sites of expression of thyroid transcription factor (TTF) -1, a transcription factor regulating formation and gene expression in the lung parenchyma. TTF-1 enhanced transcription of the mouse MK gene promoter, acting on TTF-1 regulatory elements located in the 5'-region of the gene. Furthermore, MK expression was not detected in lungs of TTF-1 null mice. TTF-1 regulates expression of MK in the lung. The temporal/spatial distribution of midkine is consistent with a potential role in paracrine signaling during lung morphogenesis.

Animals↗
PubMed2003

Paracrine action of FGF4 during periimplantation development maintains trophectoderm and primitive endoderm.

FGF4, a member of the fibroblast growth factor (FGF) family, is absolutely required for periimplantation mouse development, although its precise role at this stage remains unknown. The nature of the defect leading to postimplantation lethality of embryos lacking zygotic FGF4 is unclear and little is known about downstream targets of FGF4-initiated signaling within the various cellular compartments of the blastocyst. Here we report that postimplantation lethality of Fgf4(-/-) embryos is unlikely to reflect strictly mitogenic requirements for FGF4. Rather, our results suggest that FGF4 is required to maintain trophectoderm and primitive endoderm identity at embryonic day 4.5. This result is consistent with the reported in vitro activity of FGF4 in maintaining trophoblast stem cells and with the requirement for receptor tyrosine kinase signaling in primitive endoderm formation. Thus, postimplantation lethality of Fgf4(-/-) embryos likely results from the failure of proper differentiation and function of extraembryonic cell types.

Animals↗
PubMed2003

Endothelin-1 increases 2-arachidonoyl glycerol (2-AG) production in astrocytes.

Astrocytes play an important role in neuroprotective responses. Recent studies indicate that endothelin-1, a neuropeptide upregulated during brain injury, increases levels of the endocannabinoid anandamide, a lipid with neuroprotective properties, in astrocytes in primary cultures. However, whether this neuropeptide also alters levels of 2-arachidonoyl glycerol (2-AG), the most abundant endocannabinoid in the CNS, in astrocytes remains unknown. In addition, 2-AG levels in astrocytes have never been measured. In this report we use chemical ionization gas chromatography/mass spectrometry to quantify picomole amounts of 2-AG in primary cultures of mouse astrocytes. We also demonstrate that endothelin-1 increases 2-AG production by 5-fold in these cells, a response that requires extracellular calcium and endothelin-1(A) receptor engagement. Immunocytochemistry showed that although cultured mouse neurons and microglia express cannabinoid receptors, cultured astrocytes do not. The data suggest that endothelin-1 modulates 2-AG production in astrocytes and that this endocannabinoid may participate in paracrine signaling toward neurons and microglia.

Animals↗
PubMed2001

Mechanical trauma induces rapid astroglial activation of ERK/MAP kinase: Evidence for a paracrine signal.

Astrogliosis is a prominent and ubiquitous reaction of astrocytes to many forms of CNS injury, often implicated in the poor regenerative capacity of the adult mammalian CNS. Transmembrane signals that rapidly trigger and maintain astroglial responses to injury are largely undefined. Several candidate inducers of astrogliosis, including growth factors and neuropeptides, act via the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. We previously observed chronically activated ERK/MAPK in human reactive astrocytes. To investigate mechanisms of pathway activation in a defined in vitro model, primary cultured astroglial monolayers were subjected to focal mechanical injury. Within 2-10 min, ERK/MAPK was activated, but only in cells near the wound edge. By 30 min, the entire monolayer showed activation, which persisted for 4 to 8 h. ERK/MAPK activation was specifically blocked by application of the MEK inhibitors, PD98059 and U0126. Cell-cell contact was not necessary for intercellular spread of ERK/MAPK activation, and ERK/MAPK-stimulating activity was found in the injury-conditioned medium. The activating factor was shown to have a native size of 50-100 kD and did not signal through the classical EGF receptor. Injury-induced signaling to ERK/MAPK required Ras, as demonstrated by specific blockade after transient transfection with a dominant negative Ha-RasN17 construct. Finally, we demonstrated that focal lesioning of adult rat cortex induces a rapid activation and spreading of astroglial ERK/MAPK, suggesting that similar mechanisms may operate in astroglial activation following acute brain injury.

Animals↗
PubMed2005

Microglial EP2 is critical to neurotoxicity from activated cerebral innate immunity.

Prostaglandin (PG) E(2) acts via four functionally antagonistic E-prostanoid (EP) receptors that are expressed on multiple cell types in the nervous system; these are designated EP1-4. We showed previously that EP2 null mice are protected from CD14-dependent neuronal damage in vivo following intracerebroventricular (ICV) injection of lipopolysaccharide (LPS). Clear interpretation of this neuroprotective outcome is limited because EP2 is expressed on glia and neurons. We tested the hypothesis that microglial EP2 is required for paracrine neurotoxicity following activation of innate immunity, using primary murine microglia and neuron co-cultures. We demonstrated that microglial EP2 was necessary for lipopolysaccharide (LPS)-activated microglia-mediated neurotoxicity, as well as induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2). Genetic deletion of microglial iNOS, pharmacological suppression of COX-2 activity, or addition of exogenous superoxide dismutase (SOD) and catalase in the presence of EP2 also abolished neurotoxicity. This loss of paracrine neurotoxicity by EP2(-/-) microglia occurred in the absence of reduced cytokine levels. We conclude that microglial EP2 is critical to innate immunity-mediated paracrine damage to neurons involving COX-2 and iNOS. EP2 should be considered as a therapeutic target for suppression of microglial innate immunity-mediated damage in neurodegenerative diseases.

Animals↗
PubMed2006

Murine glia express the immunosuppressive cytokine, interleukin-10, following exposure to Borrelia burgdorferi or Neisseria meningitidis.

There is growing appreciation that resident glial cells can initiate and/or regulate inflammation following trauma or infection in the central nervous system (CNS). We have previously demonstrated the ability of microglia and astrocytes, resident glial cells of the CNS, to respond to bacterial pathogens by rapid production of inflammatory mediators. However, inflammation within the brain parenchyma is notably absent during some chronic bacterial infections in humans and nonhuman primates. In the present study, we demonstrate the ability of the immunosuppressive cytokine, interleukin-10 (IL-10), to inhibit inflammatory immune responses of primary microglia and astrocytes to B. burgdorferi and N. meningitidis, two disparate gram negative bacterial species that can cross the blood-brain barrier in humans. Importantly, we demonstrate that these organisms induce the delayed production of significant quantities of IL-10 by both microglia and astrocytes. Furthermore, we demonstrate that such production occurs independent of the actions of bacterial lipopolysaccharide and is secondary to the autocrine or paracrine actions of other glia-derived soluble mediators. The late onset of IL-10 production by resident glia following activation, the previously documented expression of specific receptors for this cytokine on microglia and astrocytes, and the ability of IL-10 to inhibit bacterially induced immune responses by these cells, suggest a mechanism by which resident glial cells can limit potentially damaging inflammation within the CNS in response to invading pathogens, and could explain the suppression of inflammation seen within the brain parenchyma during chronic bacterial infections.

Animals↗
PubMed2006

Microvascular endothelial cells increase proliferation and inhibit apoptosis of native human acute myelogenous leukemia blasts.

Interactions between acute myelogenous leukemia (AML) blasts and neighbouring endothelial cells in the bone marrow seem important both for disease development and susceptibility to chemotherapy. We investigated the effects of soluble mediators released by microvascular endothelial cells on native human AML cells. AML cells derived from 33 patients were cocultured with microvascular endothelial cells, separated by a semipermeable membrane. We investigated the effect of coculture on AML cell proliferation, viability/apoptosis and cytokine release. Coculture increased AML cell proliferation, and this growth enhancement included the clonogenic leukemia cell subset. Increased release of several soluble mediators was also detected (interleukin 3, interleukin 6, granulocyte-macrophage and granulocyte colony-stimulating factors) in cocultures. Our cytokine neutralization experiments suggest that an intercellular crosstalk involving several soluble mediators contribute to the increased leukemia cell proliferation. The presence of endothelial cells had an additional antiapoptotic effect on the AML cells. The endothelial cells did not have any growth-enhancing effect on native human acute lymphoblastic leukemia cells. Our in vitro results suggest that the release of soluble mediators by microvascular endothelial cells supports leukemic hematopoiesis through paracrine mechanisms by direct enhancement of AML blast proliferation and by inhibition of leukemic cell apoptosis.

Apoptosis↗
PubMed2007

Selective cyclooxygenase-2 inhibitor downregulates the paracrine epithelial-mesenchymal interactions of growth in scirrhous gastric carcinoma.

The importance of cancer-mesenchymal interactions in the aggressive behavior of scirrhous gastric cancer is supported by experimental and clinical evidences. We have previously reported that gastric fibroblasts secretion of keratinocyte growth factor (KGF) underline the remarkable proliferation of scirrhous gastric cancer cells. Cyclooxygenase-2 (COX-2) is not only expressed in cancer cells, but also in interstitial fibroblasts in gastric carcinoma. To clarify the mechanisms responsible for the antiproliferation effect of COX-2 inhibitors, effect of COX-2 inhibitor on the paracrine epithelial-mesenchymal interactions of growth was examined. Scirrhous gastric cancer cell line, OCUM-2M, gastric fibroblasts, NF-21, and COX-2 inhibitor, JTE-522, were used. Growth-interaction was examined by calculating the number of cancer cells or by measuring [(3)H] thymidine incorporation of cancer cells. Effect of JTE-522 on KGF expression from NF-21 cells and OCUM-2M cells was analyzed by ELISA and RT-PCR. The conditioned medium from gastric fibroblasts significantly stimulated the growth of scirrhous gastric cancer cells. JTE-522 at the concentrations of 10(-5) and 10(-6) M significantly decreased the growth-stimulating activity of gastric fibroblasts. JTE-522 reduced the expression of KGF mRNA and the production of KGF from gastric fibroblasts. Oral administration of JTE-522 significantly decreased the size of xenografted tumor coinoculated with OCUM-2M cells and NF-21 cells in nude mice. JTE-522 decreased COX-2 expression and Ki67 labeling index within the coinoculated tumor. These findings suggested that a selective COX-2 inhibitor, JTE-522, downregulates KGF production from gastric fibroblasts, resulting in the inhibition of paracrine epithelial-mesenchymal interactions of proliferation between scirrhous gastric cancer cells and gastric fibroblasts.

Animals↗
PubMed2002

Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival.

Lung cancer is currently the most frequent cause of cancer death in North America. Hepatocyte growth factor (HGF) and its receptor Met are frequently over-expressed in non-small-cell lung carcinomas (NSCLC), but their potential role in tumor progression is not clearly known. To assess the role of HGF/Met signaling in lung carcinomas, we have examined the expression, activation status, and function of Met in NSCLC cell lines (n = 7), established from primary tumors or pleural fluids of cancer patients. We observed Met expression in three NSCLC cell lines, two of which exhibited constitutive tyrosine-phosphorylation of Met, and Met kinase activity. In addition, the observed constitutive activation of Met was sustained under anchorage-independent conditions, and correlated with phosphatidyl inositol 3-kinase-dependent cell survival. Immunoreactive HGF-like protein was secreted by two Met-positive and two Met-negative NSCLC cell lines. However HGF activity, as determined by the ability to induce cell scattering and tyrosine-phosphorylation of Met in reporter cell lines, was detected in conditioned medium from only one Met-negative NSCLC cell line: none of the conditioned media from Met-expressing NSCLC cell lines showed detectable HGF activity. Thus, constitutive activation of Met in NSCLC cell lines may occur at least in part through intracrine, or HGF-independent mechanisms. Interestingly, additional paracrine stimulation with exogenous recombinant HGF was required for DNA synthesis and correlated with increased activation of ERK1/2 in all Met-positive NSCLC cell lines, regardless of the basal activation status of Met. These findings indicate that a medium level of constitutive activation of Met occurs in some NSCLC cell lines, and correlates with survival of detached carcinoma cells; whereas additional paracrine stimulation by recombinant HGF is required for DNA synthesis. Thus constitutive and paracrine activation of Met may provide complementary signals that promote survival and proliferation, respectively, during tumor progression of NSCLC.

Animals↗
PubMed2004

Vascular progenitors derived from murine bone marrow stromal cells are regulated by fibroblast growth factor and are avidly recruited by vascularizing tumors.

Bone marrow-derived stromal cells (BMSC) possess a population of vascular progenitor cells that enable them to acquire a histology and immunophenotype coherent with endothelial cells (EC). Recent evidence indicates that a hypoxic environment such as that encountered in tumor masses regulates BMSC angiogenic properties by pathways that remain to be defined. It is also unclear as to what extent these marrow-derived precursor cells could contribute to the growth of endothelium-lined vessels at the vicinity of tumor masses. In this study, we found that BMSC exhibited the ability to generate three-dimensional capillary-like networks on Matrigel, and that this property was up-regulated by growth factors-enriched conditioned media isolated from several tumor-derived cell lines. In particular, basic fibroblast growth factor, a key mediator of angiogenesis, was found to be the most potent growth factor for inducing BMSC proliferation, migration, and tubulogenesis. The setup of a new two-dimensional in vitro co-culture assay further showed that BMSC were massively recruited when cultured in the presence of either cancerous or differentiated EC lines. In vivo, subcutaneous co-injection of BMSC with U-87 glioma cells in nude mice resulted in the formation of highly vascularized tumors, where BMSC differentiated into CD31-positive cells and localized at the lumen of vascular structures. Our data suggest that BMSC could be recruited at the sites of active tumor neovascularization through paracrine regulation of their angiogenic properties. These observations may have crucial implications in the development of novel therapies using BMSC engineered to secrete anti-cancerous agents and to antagonize tumor progression.

Animals↗
PubMed2007

Elucidating progesterone effects in breast cancer: cross talk with PDGF signaling pathway in smooth muscle cell.

Several studies indicate that progesterone exerts relevant effects in breast tissue. However, the exact role of this steroid in breast cancer development and progression has not been elucidated. Here, we show that platelet-derived growth factor (PDGF)-A is one of the progesterone target genes on breast cancer MCF7 and T47D cells. A paracrine role for PDGF-A was investigated, since its receptor expression was down-regulated from breast cancer cells. Progesterone increased PDGF-A protein release as evaluated by Western blotting and ELISA. Medium from Progesterone-treated MCF7 cells resulted in phosphorylation of smooth muscle cells PDGF receptor alpha. This effect was not observed after treatment with PDGF inhibitor. MCF7 cells-secreted PDGF-A was able to increase smooth muscle cell viability and proliferation and decrease apoptosis, effects that were prevented by the use of a PDGF-A neutralizing antibody. Notably, cell invasion was not influenced by PDGF-A secreted by MCF7 cells. Our results elucidated for the first time the cross talk between progesterone and PDGF signaling pathway. The fact that MCF7-secreted PDGF elicited crucial roles in vascular wall smooth muscle cells, suggested a paracrine pathway for progesterone. Targeting these progesterone-induced processes may provide novel therapeutic strategies for hormone-dependent human breast cancer.

Apoptosis↗
PubMed2007

In vitro and in vivo osteoblastic differentiation of BMP-2- and Runx2-engineered skeletal myoblasts.

Genetic engineering with osteogenic factors is a promising approach for cell-based therapeutics and orthopedic regeneration. However, the relative efficacy of different strategies for inducing osteoblastic differentiation remains unclear and is further complicated by varied delivery vehicles, cell types, and evaluation criteria. In order to elucidate the effects of distinct gene-based strategies, we quantitatively evaluated osteoblastic differentiation and mineralization of primary skeletal myoblasts overexpressing either the BMP-2 growth factor or Runx2 transcription factor. Retroviral delivery of BMP-2 or Runx2 stimulated differentiation into an osteoblastic phenotype, as demonstrated by the induction of osteogenic gene expression, alkaline phosphatase activity, and matrix mineralization in monolayer culture and on collagen scaffolds both in vitro and in an intramuscular site in vivo. In general, BMP-2 stimulated osteoblastic markers faster and to a greater extent than Runx2, although we also identified experimental conditions under which these two factors produced similar effects. Additionally, Runx2-engineered cells did not utilize paracrine signaling via secreted osteogenic factors, in contrast to cells overexpressing BMP-2, as demonstrated by conditioned media studies and activation of Smad signaling. These results emphasize the complexity of gene therapy-based orthopedic therapeutics as an integrated relationship of differentiation state, construct maturation, and paracrine signaling of osteogenic cells. This study is significant in evaluating proposed therapeutic systems and defining a successful strategy for integrating gene medicine and orthopedic regeneration.

Animals↗
PubMed2003

Mast cell-mediated apoptosis of endothelial cells in vitro: a paracrine mechanism involving TNF-alpha-mediated down-regulation of bcl-2 expression.

Degranulated mast cells are present in the subendothelial space of eroded (de-endothelialized) coronary atheromas. Upon degranulation, mast cells secrete into the surrounding tissue an array of preformed and newly synthesized mediators, including proapoptotic molecules, such as chymase and TNF-alpha. In a co-culture system involving rat serosal mast cells and rat cardiac (microvascular) endothelial cells, we could show, by means of competitive RT-PCR, immunoblotting, immunocytochemistry, annexin staining, flow cytometry, and DNA-laddering, that stimulation of mast cells with ensuing degranulation rapidly (within 30 min) down-regulated the expression of both bcl-2 mRNA and protein, with subsequent induction of apoptosis in the endothelial cells. The major effect of bcl-2 down-regulation resided in the exocytosed granule remnants, a minor effect also being present in the granule remnant-free supernatant. No significant changes were observed in the expression levels of the pro-apoptotic protein, bax. The mast cell-mediated apoptotic effect was partially (70%) dependent on the presence of TNF-alpha and involved the translocation of cytochrome C from mitochondria into cytoplasm. These results are the first to show that one of the cell types present in the atherosclerotic plaques, namely the mast cell, by releasing both granule-remnant-bound and soluble TNF-alpha, may contribute to the erosion of atherosclerotic plaques by inducing apoptosis in adjacent endothelial cells. Published 2003 Wiley-Liss, Inc.

Animals↗
PubMed2006

Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion.

The development of hepatocellular carcinomas from malignant hepatocytes is frequently associated with intra- and peritumoral accumulation of connective tissue arising from activated hepatic stellate cells. For both tumorigenesis and hepatic fibrogenesis, transforming growth factor (TGF)-beta signaling executes key roles and therefore is considered as a hallmark of these pathological events. By employing cellular transplantation we show that the interaction of neoplastic MIM-R hepatocytes with the tumor microenvironment, containing either activated hepatic stellate cells (M1-4HSCs) or myofibroblasts derived thereof (M-HTs), induces progression in malignancy. Cotransplantation of MIM-R hepatocytes with M-HTs yielded strongest MIM-R generated tumor formation accompanied by nuclear localization of Smad2/3 as well as of beta-catenin. Genetic interference with TGF-beta signaling by gain of antagonistic Smad7 in MIM-R hepatocytes diminished epithelial dedifferentiation and tumor progression upon interaction with M1-4HSCs or M-HTs. Further analysis showed that tumors harboring disrupted Smad signaling are devoid of nuclear beta-catenin accumulation, indicating a crosstalk between TGF-beta and beta-catenin signaling. Together, these data demonstrate that activated HSCs and myofibroblasts directly govern hepatocarcinogenesis in a TGF-beta dependent fashion by inducing autocrine TGF-beta signaling and nuclear beta-catenin accumulation in neoplastic hepatocytes. These results indicate that intervention with TGF-beta signaling is highly promising in liver cancer therapy.

Animals↗
PubMed2003

Perturbations in paracrine control of the circulation: role of the endothelial-derived vasomediators, endothelin-1 and nitric oxide.

Central to the control of vascular resistance in the systemic and pulmonary circulation and at the solid organ level is the function of the endothelial-derived vasomediators, endothelin-1 (ET-1) and nitric oxide. Regulation of steady-state levels of ET-1 and endothelial nitric oxide synthase (eNOS) mRNAs represents an early and influential step in their biosynthesis and is highly responsive to exogenous stimuli. ET-1 is expressed from a rapidly inducible promoter to generate a highly labile mRNA. Conversely, the eNOS promoter generates a constitutive level of a very stable mRNA and utilizes posttranscriptional mechanisms to modulate mRNA expression. The response of these genes in models of cellular activation commonly reflects a reciprocal pattern of regulation, namely, transcriptional induction of ET-1 and destabilization of the eNOS mRNA. Elucidating the mechanisms influencing ET-1 and eNOS mRNA is providing novel insight into endothelial gene regulation and providing opportunities for future therapeutic strategies.

Animals↗
PubMed2003

Paracrine interactions of mammalian adipose tissue.

Adipose tissue develops in and/or around most lymphoid tissues in mammals and birds. Early reports of this widespread association and hypotheses for its functional basis were long ignored in the planning of in vitro studies and the interpretation of in vivo results. Biochemical studies on rodent tissues reveal many site-specific properties of adipocytes anatomically associated with lymph nodes and omental milky spots that equip them to interact locally with lymphoid cells. The paracrine interactions are strongest for the most readily activated lymph nodes and are modulated by dietary lipids. Perinodal adipocytes contribute less than those in the large nodeless depots to whole-body lipid supplies during fasting. Observations on wild animals show that perinodal adipose tissue is selectively conserved even in starvation but does not enlarge greatly in natural obesity. Such paracrine provisioning of peripheral immune responses improves their efficiency and emancipates activated lymphocytes from competition with other tissues for blood-borne nutrients. The relationship is found in extant protherians and metatherians, so it almost certainly arose early in the evolution of mammals, possibly as part of the metabolic reorganisation associated with homeothermy, viviparity, and lactation. Prolonged disruption to paracrine interactions between lymphoid and adipose tissue may contribute to the HIV-associated adipose redistribution syndrome, causing selective hypertrophy of the mesentery, omentum, and other adipose depots that contain much activated lymphoid tissue. Skeletal and cardiac muscle may also have paracrine relationships with anatomically associated adipose tissue, but interactions between contiguous tissues have not been demonstrated directly.

Adipose Tissue↗