Jupiter's atmospheric jet streams extend thousands of kilometres deep.

The depth to which Jupiter's observed east-west jet streams extend has been a long-standing question. Resolving this puzzle has been a primary goal for the Juno spacecraft, which has been in orbit around the gas giant since July 2016. Juno's gravitational measurements have revealed that Jupiter's gravitational field is north-south asymmetric, which is a signature of the planet's atmospheric and interior flows. Here we report that the measured odd gravitational harmonics J3, J5, J7 and J9 indicate that the observed jet streams, as they appear at the cloud level, extend down to depths of thousands of kilometres beneath the cloud level, probably to the region of magnetic dissipation at a depth of about 3,000 kilometres. By inverting the measured gravity values into a wind field, we calculate the most likely vertical profile of the deep atmospheric and interior flow, and the latitudinal dependence of its depth. Furthermore, the even gravity harmonics J8 and J10 resulting from this flow profile also match the measurements, when taking into account the contribution of the interior structure. These results indicate that the mass of the dynamical atmosphere is about one per cent of Jupiter's total mass.

A suppression of differential rotation in Jupiter's deep interior.

Jupiter's atmosphere is rotating differentially, with zones and belts rotating at speeds that differ by up to 100 metres per second. Whether this is also true of the gas giant's interior has been unknown, limiting our ability to probe the structure and composition of the planet. The discovery by the Juno spacecraft that Jupiter's gravity field is north-south asymmetric and the determination of its non-zero odd gravitational harmonics J3, J5, J7 and J9 demonstrates that the observed zonal cloud flow must persist to a depth of about 3,000 kilometres from the cloud tops. Here we report an analysis of Jupiter's even gravitational harmonics J4, J6, J8 and J10 as observed by Juno and compared to the predictions of interior models. We find that the deep interior of the planet rotates nearly as a rigid body, with differential rotation decreasing by at least an order of magnitude compared to the atmosphere. Moreover, we find that the atmospheric zonal flow extends to more than 2,000 kilometres and to less than 3,500 kilometres, making it fully consistent with the constraints obtained independently from the odd gravitational harmonics. This depth corresponds to the point at which the electric conductivity becomes large and magnetic drag should suppress differential rotation. Given that electric conductivity is dependent on planetary mass, we expect the outer, differentially rotating region to be at least three times deeper in Saturn and to be shallower in massive giant planets and brown dwarfs.

Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response.

The generation of animals lacking SMAD proteins, which transduce signals from transforming growth factor-beta (TGF-beta), has made it possible to explore the contribution of the SMAD proteins to TGF-beta activity in vivo. Here we report that, in contrast to predictions made on the basis of the ability of exogenous TGF-beta to improve wound healing, Smad3-null (Smad3ex8/ex8) mice paradoxically show accelerated cutaneous wound healing compared with wild-type mice, characterized by an increased rate of re-epithelialization and significantly reduced local infiltration of monocytes. Smad3ex8/ex8 keratinocytes show altered patterns of growth and migration, and Smad3ex8/ex8 monocytes exhibit a selectively blunted chemotactic response to TGF-beta. These data are, to our knowledge, the first to implicate Smad3 in specific pathways of tissue repair and in the modulation of keratinocyte and monocyte function in vivo.

Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing.

Secretory leukocyte protease inhibitor (SLPI) is a serine protease inhibitor with anti-microbial properties found in mucosal fluids. It is expressed during cutaneous wound healing. Impaired healing states are characterized by excessive proteolysis and often bacterial infection, leading to the hypothesis that SLPI may have a role in this process. We have generated mice null for the gene encoding SLPI (Slpi), which show impaired cutaneous wound healing with increased inflammation and elastase activity. The altered inflammatory profile involves enhanced activation of local TGF-beta in Slpi-null mice. We propose that SLPI is a pivotal endogenous factor necessary for optimal wound healing.

HIV infection and specific mucosal immunity: workshop 4B.

Most HIV infections are transmitted across mucosal epithelium. An area of fundamental importance is understanding the role of innate and specific mucosal immunity in susceptibility or protection against HIV infection, as well as the effect of HIV infection on mucosal immunity, which leads to increased susceptibility to bacterial, fungal, and viral infections of oral and other mucosae. This workshop attempted to address 5 basic issues-namely, HIV acquisition across mucosal surfaces, innate and adaptive immunity in HIV resistance, antiviral activity of breast milk as a model mucosal fluid, neutralizing immunoglobulin A antibodies against HIV, and progress toward a mucosal vaccine against HIV. The workshop attendants agreed that progress had been made in each area covered, with much recent information. However, these advances revealed how little work had been performed on stratified squamous epithelium compared with columnar epithelium, and the attendants identified several important biological questions that had not been addressed. It is increasingly clear that innate immunity has an important biological role, although basic understanding of the mechanisms of normal homeostasis is still being investigated. Application of the emerging knowledge was lacking with regard to homeostatic mucosal immunity to HIV and its role in changing this homeostasis. With regard to breast milk, a series of studies have demonstrated the differences between transmitters and nontransmitters, although whether these findings could be generalized to other secretions such as saliva was less clear. Important progress toward an oral mucosal HIV vaccine has been made, demonstrating proof of principle for administering vaccine candidates into oral lymphoid tissues to trigger anti-HIV local and systemic immune responses. Similarly, experimental data emphasized the central role of neutralizing antibodies to prevent HIV infection via mucosal routes.

Role of B lymphocytes in cell-mediated immunity. I. Requirement for T cells or T-cell products for antigen-induced B-cell activation.

Although B lymphocytes can be triggered by B-cell mitogens and by certain other molecules to produce lymphokines, they do not produce lymphokines when stimulated with specific soluble protein antigens. We have investigated whether T-cell help would enable B cells to produce lymphokines when activated by antigens. Addition of small numbers of T cells to B-cell cultures resulted in significant production of a monocyte chemotactic factor. T cells could be replaced by supernates of antigen-stimulated T cells, demonstrating both that the chemotactic factor was B-cell-dervied and that T-cell help was mediated by a soluble factor. Although the T-cell factor was nonantigen specific, B-cell activation required the presence of both antigen and T-cell factor. Thus, it appears that although dependent upon T cells, B lymphocytes may play an important role in amplification of cell-mediated immune responses.

Engagement of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells.

Evidence indicates that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. CD4(+) T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF-beta after antibody cross-linking of CTLA-4, indicating that induction of TGF-beta by CTLA-4 signaling represents a ubiquitous feature of murine CD4(+) T cells. Stimulation of the CD3-T cell antigen receptor complex does not independently induce TGF-beta, but is required for optimal CTLA-4-mediated TGF-beta production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon gamma (Th1) and IL-4 (Th2). Moreover, addition of anti-TGF-beta partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-beta1 gene-deleted (TGF-beta1(-/-)) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4(+) T cell production of TGF-beta, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-beta, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4(+) T cell activation.

Induction of guinea pig B-cell lymphokine synthesis by mitogenic and nonmitogenic signals to Fc, Ig, and C3 receptors.

This study shows that bone marrow-derived lymphocytes of guinea pigs if appropriately activated produce a monocyte chemotactic factor (MNL CTX). Activation of B lymphocytes to produce a chemotactic lymphokine occurs subsequent to interactions with a variety of membrane-associated receptors. Polymeric B-cell mitogens with multiple binding sites, polymerized flagellin and lipopolysaccharide, initiated mediator synthesis. Furthermore, interaction of antigen-antibody complexes or aggregated gamma globulin with the Fc receptor and binding of antigen-antibody-complement complexes at the C3 receptor can effectively facilitate mediator production in the absence of a significant proliferative response. Additionally, intact anti-immunoglobulin but not its Fab fragments activated the B cells. An anti-Fab effectively converted the inactive Fab-bound B cells into producers of MNL CTX, suggesting that the basic mechanism of activation depended upon cross-linking of receptors. Thus, interaction of B-cell surface receptors such as Fc, Ig, and C3 sites with mitogenic as well as nonmitogenic molecules capable of bridging the receptors appears to trigger B-cell mediator production.

Spontaneous production of fibroblast-activating factor(s) by synovial inflammatory cells. A potential mechanism for enhanced tissue destruction.

A characteristic feature of rheumatoid arthritis is hyperplasia of the synovial lining cells and fibroblasts, the source of tissue-degrading mediators, in association with the appearance and persistence of lymphocytes in affected joints. Diseased synovial tissue obtained at arthroscopy from 10 of 12 rheumatoid arthritis patients was found to release a factor(s) that could stimulate quiescent fibroblasts to proliferate in vitro. Mononuclear cells isolated from this synovial tissue and from the synovial fluid spontaneously produced fibroblast-activating factor(s) (FAF). In contrast, synovial tissue from patients with noninflammatory joint disease did not release FAF. By gel filtration, FAF was detected in two peaks (40,000 and 15,000 mol wt) that were consistent with the previously described peripheral blood T lymphocyte- and monocyte-derived factors with identical activity. The mononuclear cells were predominantly OKT3+/Leu-1+ T lymphocytes and OKM1+ cells of monocyte/macrophage lineage that expressed HLA-DR antigens, suggesting prior activation of these cells. Mononuclear cells isolated from the peripheral blood of these patients did not spontaneously secrete FAF. Lymphocytes and monocytes from the site of synovial inflammation appear to be activated in situ to produce factors that may contribute to the hyperplasia and overgrowth of the synovial membrane in rheumatoid arthritis.

Reversal of acute and chronic synovial inflammation by anti-transforming growth factor beta.

Transforming growth factor beta (TGF-beta) induces leukocyte recruitment and activation, events central to an inflammatory response. In this study, we demonstrate that antagonism of TGF-beta with a neutralizing antibody not only blocks inflammatory cell accumulation, but also tissue pathology in an experimental model of chronic erosive polyarthritis. Intraarticular injection of monoclonal antibody 1D11.16, which inhibits both TGF-beta 1 and TGF-beta 2 bioactivity, into animals receiving an arthropathic dose of bacterial cell walls significantly inhibits arthritis. Inhibition was observed with a single injection of 50 micrograms antibody, and a 1-mg injection blocked acute inflammation > 75% compared with the contralateral joints injected with an irrelevant isotype control antibody (MOPC21) as quantitated by an articular index (AI = 0.93 +/- 0.23 for 1D11.16, and AI = 4.0 +/- 0 on day 4; p < 0.001). Moreover, suppression of the acute arthritis achieved with a single injection of antibody was sustained into the chronic, destructive phase of the disease (on day 18, AI = 0.93 +/- 0.07 vs. AI = 2.6 +/- 0.5; p < 0.01). The decreased inflammatory index associated with anti-TGF-beta treatment was consistent with histopathologic and radiologic evidence of a therapeutic response. These data implicate TGF-beta as a profound agonist not only in the early events responsible for synovial inflammation, but also in the chronicity of streptococcal cell wall fragment-induced inflammation culminating in destructive pathology. Interrupting the cycle of leukocyte recruitment and activation with TGF-beta antagonists may provide a mechanism for resolution of chronic destructive lesions.

Interleukin (IL) 4 differentially regulates monocyte IL-1 family gene expression and synthesis in vitro and in vivo.

Interleukin (IL) 4 is a multifunctional T cell-derived cytokine that inhibits cytokine production and certain effector functions in human monocytes, while enhancing others. We show that IL-4 may contribute to the downregulation and resolution of an inflammatory response by selectively promoting expression of the IL-1 receptor antagonist (IL-1ra) that blocks the action of IL-1. IL-1ra specifically binds to the IL-1 receptor without initiating signal transduction. Peripheral blood monocytes obtained from cancer patients, before and immediately after a regimen of IL-4 immunotherapy, were examined for IL-1ra gene expression. After IL-4 therapy, monocytes from the patients showed a marked increase in IL-1ra mRNA. This selective induction of IL-1ra mRNA in circulating monocytes was reflected by significantly enhanced serum levels of IL-1ra (p < 0.01) during IL-4 therapy, which declined after IL-4 treatment. In vitro analysis of IL-4 regulation of monocytes from normal individuals revealed a dose-dependent induction of IL-1ra mRNA within 2-4 h after stimulation without a concomitant effect on the expression of IL-1 mRNA. Increased IL-1ra mRNA was not due to RNA stabilization, but occurred at the level of transcription. In the presence of LPS, IL-4 not only augmented IL-1ra levels, but markedly inhibited LPS-induced IL-1 mRNA expression. The selective upregulation of IL-1ra by resting or activated monocytes, coupled with inhibition of IL-1 production by activated monocytes, as we demonstrate both in vitro and in vivo, suggests that IL-4 may prove clinically useful as a systemic antiinflammatory agent.

Suppression of arthritis by an inhibitor of nitric oxide synthase.

Nitric oxide (NO), a toxic radical gas produced during the metabolism of L-arginine by NO synthase (NOS), has been implicated as a mediator of immune and inflammatory responses. A single injection of streptococcal cell wall fragments (SCW) induces the accumulation of inflammatory cells within the synovial tissue and a cell-mediated immune response that leads destructive lesions. We show here that NO production is elevated in the inflamed joints of SCW-treated rats. Administration of NG-monomethyl-L-arginine, an inhibitor of NOS, profoundly reduced the synovial inflammation and tissue damage as measured by an articular index and reflected in the histopathology. These studies implicate the NO pathway in the pathogenesis of an inflammatory arthritis and demonstrate the ability of a NOS inhibitor to modulate the disease.

Bacterial cell wall-induced hepatic granulomas. An in vivo model of T cell-dependent fibrosis.

In vitro studies implicate a molecular link between inflammatory mononuclear cells and alterations in fibroblast growth and function. We have extended these observations in an experimental animal model in which we document the T cell-dependence of fibrosis that occurs after activation of the cell-mediated immune system by specific antigen. Chronic granulomatous lesions were induced in the livers of susceptible rats by the intraperitoneal injection of group A streptococcal cell walls (SCW). The development of granulomas that are composed primarily of lymphocytes and macrophages was associated with the recruitment and proliferation of connective tissue cells. Furthermore, this expanded population of fibroblasts generated a collagenous structure consisting primarily of types I and III collagen around the granuloma. The progression of these chronic inflammatory lesions leads to the formation of fibrotic nodules throughout the livers of the treated animals. Intact granulomas, as well as mononuclear cells derived from the granulomas, spontaneously elaborated a soluble factor(s) that stimulates fibroblast proliferation. Physicochemical analysis revealed that the primary granuloma-derived peak of fibroblast growth activity corresponded to an apparent Mr of 40,000, which is consistent with a previously described T lymphocyte--derived fibroblast-activating factor (FAF) in guinea pig and human. Furthermore, the fibrosis that occurs in the granuloma is apparently T cell--dependent, since no fibrotic lesions developed in SCW-injected athymic nude rats nor in SCW-injected animals treated with the T cell inhibitor, cyclosporin A (CsA). Mononuclear cells from neither of these functionally T cell--deficient animals could generate FAF activity. These data show a role for T lymphocyte--derived cytokines in the development of hepatic fibrosis in SCW-injected rats.

Surface proteins from Helicobacter pylori exhibit chemotactic activity for human leukocytes and are present in gastric mucosa.

The mechanism by which Helicobacter pylori, a noninvasive bacterium, initiates chronic antral gastritis in humans is unknown. We now show that H. pylori releases products with chemotactic activity for monocytes and neutrophils. This chemotactic activity was inhibited by antisera to either H. pylori whole bacteria or H. pylori-derived urease. Moreover, surface proteins extracted from H. pylori and purified H. pylori urease (a major component of the surface proteins) exhibited dose-dependent, antibody-inhibitable chemotactic activity. In addition, a synthetic 20-amino acid peptide from the NH2-terminal portion of the 61-kD subunit, but not the 30-kD subunit, of urease exhibited chemotactic activity for monocytes and neutrophils, localizing the chemotactic activity, at least in part, to the NH2 terminus of the 61-kD subunit of urease. The ability of leukocytes to chemotax to H. pylori surface proteins despite formyl-methionyl-leucyl-phenylalanine (FMLP) receptor saturation, selective inhibition of FMLP-mediated chemotaxis, or preincubation of the surface proteins with antiserum to FMLP indicated that the chemotaxis was not FMLP mediated. Finally, we identified H. pylori surface proteins and urease in the lamina propria of gastric antra from patients with H. pylori-associated gastritis but not from uninfected subjects. These findings suggest that H. pylori gastritis is initiated by mucosal absorption of urease, which expresses chemotactic activity for leukocytes by a mechanism not involving N-formylated oligopeptides.

Bacterial cell wall-induced immunosuppression. Role of transforming growth factor beta.

Group A streptococcal cell wall (SCW)-injected rats exhibit a profound immunosuppression that persists for months after the initial intraperitoneal injection of SCW. The goal of this study was to determine the mechanisms for the suppressed T lymphocyte proliferative responses in this experimental model of chronic inflammation. When spleen cell preparations were depleted of adherent cells, restoration of T cell proliferative responses to Con A and PHA occurred, implicating adherent macrophages in the regulation of immunosuppression. Furthermore, macrophages from SCW-treated animals, when cocultured with normal spleen cells in the presence of Con A or PHA, effectively inhibited the proliferative response. Supernatants from suppressed spleen cell cultures were found to inhibit normal T cell mitogenesis. Taken together, these results implicated a soluble macrophage-derived suppressor factor in the down regulation of T cell proliferation after exposure to SCW in vivo. Subsequent in vitro studies to identify this suppressor molecule(s) revealed the activity to be indistinguishable from the polypeptide transforming growth factor beta (TGF-beta). Furthermore, TGF-beta was identified by immunolocalization within the spleens of SCW-injected animals. The cells within the spleen that stained positively for TGF-beta were phagocytic cells that had ingested, and were presumably activated by, the SCW. These studies document that TGF-beta, previously shown to be a potent immunosuppressive agent in vitro, also effectively inhibits immune function in chronic inflammatory lesions in vivo.

Rapid onset synovial inflammation and hyperplasia induced by transforming growth factor beta.

After intraarticular injection of TGF-beta 1 or TGF-beta 2, marked swelling and erythema of the injected joints were apparent within 12-24 h. On a scale of 0 to 4, by day 3, the TGF-beta-treated joints had articular indices (AI) of 3.6 +/- 0.5 to 4.0 +/- 0.0 compared with no response for the vehicle-injected contralateral joints. Histopathologic evaluation revealed a predominantly mononuclear phagocyte infiltrate with some neutrophils and T lymphocytes, consistent with active inflammation. The monocytic pattern of leukocyte infiltration at 2-3 d was comparable to that seen in animals with antigen-induced arthritis after 2-3 wk. Extensive synovial fibroblast hyperplasia became apparent within 48 h, likely as a result of TGF-beta induction of growth factor synthesis by the accumulating monocytes. TGF-beta 2, a homologue of TGF-beta 1, was found to induce a similar level of synovitis and synovial hyperplasia consistent with its parallel monocyte and fibroblast chemotactic properties and ability to induce transcription and translation of monocyte/macrophage-derived growth factors. These data suggest that TGF-beta, released by platelets and activated inflammatory cells, may play a direct role in leukocyte recruitment and activation in arthritic and other chronic inflammatory lesions.

Requirement for transforming growth factor beta1 in controlling T cell apoptosis.

Transforming growth factor (TGF)-beta1, a potent immunoregulatory molecule, was found to control the life and death decisions of T lymphocytes. Both thymic and peripheral T cell apoptosis was increased in mice lacking TGF-beta1 (TGF-beta1(-/-)) compared with wild-type littermates. Engagement of the T cell receptor enhanced this aberrant T cell apoptosis, as did signaling through either the death receptor Fas or the tumor necrosis factor alpha receptor in peripheral T cells. Strikingly, TGF-beta was localized within the mitochondria of normal T cells, and the absence of TGF-beta1 resulted in disruption of mitochondrial membrane potential (Deltapsi(m)), which marks the point of no return in a cell condemned to die. This TGF-beta-dependent regulation of viability appears dissociable from the TGF-beta1 membrane receptor-Smad3 signaling pathway, but associated with a mitochondrial antiapoptotic protein Bcl-XL. Thus, TGF-beta1 may protect T cells at multiple sites in the death pathway, particularly by maintaining the essential integrity of mitochondria. These findings may have broad implications not only for T cell selection and death in immune responses and in the generation of tolerance, but also for defining the mechanisms of programmed cell death in general.

Macrophage- and astrocyte-derived transforming growth factor beta as a mediator of central nervous system dysfunction in acquired immune deficiency syndrome.

The multifunctional cytokine, transforming growth factor beta (TGF-beta), was identified by immunocytochemistry in the brain tissues of four patients with acquired immune deficiency syndrome (AIDS), but not in control brain tissue. The TGF-beta staining was localized to cells of monocytic lineage as well as astrocytes, especially in areas of brain pathology. In addition, the brain tissues from the AIDS patients contained transcripts for human immunodeficiency virus 1 (HIV-1) by in situ hybridization, suggesting a correlation between the presence of HIV-1 in the brain and the expression of TGF-beta. However, the expression of TGF-beta was not limited to HIV-1-positive cells, raising the possibility of alternative mechanisms for the induction of TGF-beta in these AIDS patients' brains. To investigate these mechanisms, purified human monocytes were infected in vitro with HIV-1 and were shown to secrete increased levels of TGF-beta. In addition, HIV-1-infected monocytes released a factor(s) capable of triggering cultured astrocytes that are not infected with HIV-1 to secrete TGF-beta. The release of TGF-beta, which is an extremely potent chemotactic factor, may contribute to the recruitment of HIV-1-infected monocytic cells, enabling viral spread to and within the central nervous system (CNS). Moreover, TGF-beta augments cytokine production, including cytokines known to be neurotoxic. The identification of TGF-beta within the CNS implicates this cytokine in the immunopathologic processes responsible for AIDS-related CNS dysfunction.

Secretory leukocyte protease inhibitor suppresses the inflammation and joint damage of bacterial cell wall-induced arthritis.

Disruption of the balance between proteases and protease inhibitors is often associated with pathologic tissue destruction. To explore the therapeutic potential of secretory leukocyte protease inhibitor (SLPI) in erosive joint diseases, we cloned, sequenced, and expressed active rat SLPI, which shares the protease-reactive site found in human SLPI. In a rat streptococcal cell wall (SCW)-induced model of inflammatory erosive polyarthritis, endogenous SLPI was unexpectedly upregulated at both mRNA and protein levels in inflamed joint tissues. Systemic delivery of purified recombinant rat SLPI inhibited joint inflammation and cartilage and bone destruction. Inflammatory pathways as reflected by circulating tumor necrosis factor alpha and nuclear factor kappaB activation and cartilage resorption detected by circulating levels of type II collagen collagenase-generated cleavage products were all diminished by SLPI treatment in acute and chronic arthritis, indicating that the action of SLPI may extend beyond inhibition of serine proteases.

Macrophages as a source of HIV during opportunistic infections.

The source of increasing viremia that characterizes the latter stages of human immunodeficiency virus (HIV) disease has remained a paradox because it occurs at a time when lymphoid tissue is quantitatively and qualitatively impaired, and the patients' CD4 T lymphocytes are steadily declining. Here, macrophages, both infected and uninfected with common opportunistic pathogens of HIV disease such as Mycobacterium avium complex and Pneumocystis carinii, were identified as highly productive sources of HIV in coinfected lymph nodes. These observations indicate that tissue macrophages are not only infected with HIV, but that common pathogens of HIV disease can dramatically increase their production of virus. Thus, prevention or successful treatment of opportunistic coinfections, or both, potentially benefits the patient twofold by limiting the pathology caused by opportunistic infection and by controlling induction of HIV replication.