Inflammation induced by tumor-associated nerves promotes resistance to anti-PD-1 therapy in cancer patients and is targetable by interleukin-6 blockade.

While the nervous system has reciprocal interactions with both cancer and the immune system, little is known about the potential role of tumor associated nerves (TANs) in modulating anti-tumoral immunity. Moreover, while peri-neural invasion is a well establish poor prognostic factor across cancer types, the mechanisms driving this clinical effect remain unknown. Here, we provide clinical and mechniastic association between TANs damage and resistance to anti-PD-1 therapy. Using electron microscopy, electrical conduction studies, and tumor samples of cutaneous squamous cell carcinoma (cSCC) patients, we showed that cancer cells can destroy myelin sheath and induce TANs degeneration. Multi-omics and spatial analyses of tumor samples from cSCC patients who underwent neoadjuvant anti-PD-1 therapy demonstrated that anti-PD-1 non-responders had higher rates of peri-neural invasion, TANs damage and degeneration compared to responders, both at baseline and following neoadjuvant treatment. Tumors from non-responders were also characterized by a sustained signaling of interferon type I (IFN-I) - known to both propagate nerve degeneration and to dampen anti-tumoral immunity. Peri-neural niches of non-responders were characterized by higher immune activity compared to responders, including immune-suppressive activity of M2 macrophages, and T regulatory cells. This tumor promoting inflammation expanded to the rest of the tumor microenvironment in non-responders. Anti-PD-1 efficacy was dampened by inducing nerve damage prior to treatment administration in a murine model. In contrast, anti-PD-1 efficacy was enhanced by denervation and by interleukin-6 blockade. These findings suggested a potential novel anti-PD-1 resistance drived by TANs damage and inflammation. This resistance mechanism is targetable and may have therapeutic implications in other neurotropic cancers with poor response to anti-PD-1 therapy such as pancreatic, prostate, and breast cancers.

The CSF in neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells.

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders.

Targeted suppression of gibberellin biosynthetic genes ZmGA20ox3 and ZmGA20ox5 produces a short stature maize ideotype.

Maize is one of the world's most widely cultivated crops. As future demands for maize will continue to rise, fields will face ever more frequent and extreme weather patterns that directly affect crop productivity. Development of environmentally resilient crops with improved standability in the field, like wheat and rice, was enabled by shifting the architecture of plants to a short stature ideotype. However, such architectural change has not been implemented in maize due to the unique interactions between gibberellin (GA) and floral morphology which limited the use of the same type of mutations as in rice and wheat. Here, we report the development of a short stature maize ideotype in commercial hybrid germplasm, which was generated by targeted suppression of the biosynthetic pathway for GA. To accomplish this, we utilized a dominant, miRNA-based construct expressed in a hemizygous state to selectively reduce expression of the ZmGA20ox3 and ZmGA20ox5 genes that control GA biosynthesis primarily in vegetative tissues. Suppression of both genes resulted in the reduction of GA levels leading to inhibition of cell elongation in internodal tissues, which reduced plant height. Expression of the miRNA did not alter GA levels in reproductive tissues, and thus, the reproductive potential of the plants remained unchanged. As a result, we developed a dominant, short-stature maize ideotype that is conducive for the commercial production of hybrid maize. We expect that the new maize ideotype would enable more efficient and more sustainable maize farming for a growing world population.

The Transcription Factor Lrp of Pantoea stewartii subsp. stewartii Controls Capsule Production, Motility, and Virulence Important for in planta Growth.

The bacterial phytopathogen Pantoea stewartii subsp. stewartii causes leaf blight and Stewart's wilt disease in susceptible corn varieties. A previous RNA-Seq study examined P. stewartii gene expression patterns during late-stage infection in the xylem, and a Tn-Seq study using a P. stewartii mutant library revealed genes essential for colonization of the xylem. Based on these findings, strains with in-frame chromosomal deletions in the genes encoding seven transcription factors (NsrR, IscR, Nac, Lrp, DSJ_00125, DSJ_03645, and DSJ_18135) and one hypothetical protein (DSJ_21690) were constructed to further evaluate the role of the encoded gene products during in vitro and in planta growth. Assays for capsule production and motility indicate that Lrp plays a role in regulating these two key physiological outputs in vitro. Single infections of each deletion strain into the xylem of corn seedlings determined that Lrp plays a significant role in P. stewartii virulence. In planta xylem competition assays between co-inoculated deletion and the corresponding complementation or wild-type strains as well as in vitro growth curves determined that Lrp controls functions important for P. stewartii colonization and growth in corn plants, whereas IscR may have a more generalized impact on growth. Defining the role of essential transcription factors, such as Lrp, during in planta growth will enable modeling of key components of the P. stewartii regulatory network utilized during growth in corn plants.

Ion Dissociation Dynamics of 1,2,3,4-Tetrahydronaphthalene: Tetralin as a Test Case For Hydrogenated Polycyclic Aromatic Hydrocarbons.

The unimolecular dissociation of ionized tetralin was probed by tandem mass spectrometry, imaging photoelectron photoion coincidence (iPEPICO) spectroscopy, and theory. The major reactions observed were the loss of the hydrocarbons CH3•, C2H4, and C3H5• together with H•-atom loss. RRKM modeling of the iPEPICO data suggested a two-well potential energy surface. Ionized tetralin can lose all four neutrals via H-shift and ring-opening reactions or CH3• and C2H4 after interconversion to the 1-methylindane ion, a process similar to that found for ionized 1,2-dihydronaphthalene (isomerizing to form the 1-methylindene ion structure). This was confirmed at the B3LYP/6-31+G(d,p) level of theory, and potential mechanisms for all reactions are described. The ionization energy of tetralin was established from the threshold photoelectron spectrum to be 8.46 ± 0.01 eV.

Hydroxy-Substituted Polycyclic Aromatic Hydrocarbon Ions as Sources of CO and HCO in the Interstellar Medium.

Tandem mass spectrometry was used to explore the trends in the unimolecular fragmentation of the ionized hydroxy-substituted polycyclic aromatic hydrocarbons 1-naphthol, 9-hydroxyphenanthrene, and 1-hydroxypyrene. The main dissociation reactions across all ring systems were CO- and HCO-losses, with ionized 1-naphthol also losing H atoms. Both ionized 1-naphthol and 9-hydroxyphenanthrene displayed the sequential loss of C2H2 and C4H2 from the [M-HCO]+ ions, reminiscent of unsubstituted PAH ions. CO-loss is slightly favored for 1-naphthol and 9-hydroxyphenanthrene, at low collision energy, but less so for 1-hydroxypyrene. Reaction mechanisms for HCO- and CO-losses from 1-hydroxypyrene were derived from CCSD/6-31G(d)//B3-LYP/6-31G(d) calculations. The CO-loss mechanism is dominated by two transition states: TS-A governing a 1,3-H shift in the molecular ion and TS-C which governs a ring-closing step to form a five-member ring in the product ion. HCO-loss occurs over a much flatter potential energy surface with the intermediate being the product ion bound to the carbon atom of HCO. Imaging photoelectron photoion coincidence spectroscopy of 1-hydroxypyrene yielded threshold photon-energy resolved breakdown curves and time-of-flight distributions that were modeled with RRKM theory to give 0 K reaction energies for HCO- and CO-losses of 3.92 ± 0.05 and 2.91 ± 0.05 eV, respectively. The entropies of activation for the two channels were very different, 14 and 95 JK-1 mol-1, respectively, a result consistent with the calculated mechanisms. The threshold photoelectron spectrum yielded an IE value of 7.14 ± 0.01 eV for 1-hydroxypyrene.

Epidemiology of Deltacoronaviruses (δ-CoV) and Gammacoronaviruses (γ-CoV) in Wild Birds in the United States.

Porcine deltacoronavirus (δ-CoV) is the object of extensive research in several countries including the United States. In contrast, the epidemiology of δ-CoVs in wild birds in the US is largely unknown. Our aim was to comparatively assess the prevalence of δ- and γ-CoVs in wild migratory terrestrial and aquatic birds in Arkansas, Illinois, Indiana, Maryland, Mississippi, Missouri, Ohio, Tennessee and Wisconsin. A total of 1236 cloacal/fecal swabs collected during the period 2015-2018 were tested for γ- and δ-CoVs using genus-specific reverse transcription-PCR assays. A total of 61 (4.99%) samples were γ-CoV positive, with up to 29 positive samples per state. In contrast, only 14 samples were positive for δ-CoV (1.14%) with only 1-4 originating from the same state. Thus, unlike previous reports from Asia, γ-CoVs are more prevalent than δ-CoVs in the US, suggesting that δ-CoVs may spread in birds with lower efficiency. This may indicate δ-CoV emerging status and incomplete adaptation to new host species limiting its spread. Phylogenetic analysis of the partial N gene revealed that the newly identified δ-CoV strains were most closely related to the HKU20 (wigeon) strain. Further studies are necessary to investigate the role of aquatic bird δ-CoVs in the epidemiology of δ-CoVs in swine and terrestrial birds.

Novel Mammalian orthorubulavirus 5 Discovered as Accidental Cell Culture Contaminant.

A distinct Russian Mammalian orthorubulavirus 5 (PIV5) was detected in cell culture exhibiting cytopathic effect and hypothesized to be contaminated by a scientist with respiratory symptoms. The identification of the divergent strain indicated a lack of knowledge on the diversity of PIV5 strains and calls for surveillance of global PIV5 strains.

What Will Photo-Processing of Large, Ionized Amino-Substituted Polycyclic Aromatic Hydrocarbons Produce in the Interstellar Medium?

Collision-energy resolved tandem mass spectrometry was used to probe the trends in unimolecular fragmentation in a series of ionized amino-substituted polycyclic aromatic hydrocarbons ranging from naphthalene to pyrene. As the ring system expands, the dominant dissociation process changes from HNC loss (aniline) to H loss for 1-aminopyrene. Imaging photoelectron photoion coincidence spectroscopy of 1-aminopyrene yielded threshold photon-energy resolved breakdown curves, the Rice-Ramsperger-Kassel-Marcus modeling of which gave a 0 K activation energy, E0, for H loss of 3.8 ± 0.4 eV. Calculations at the CCSD/6-31G(d)//B3LYP/6-31G(d) level of theory were used to explore the possible reaction mechanisms for H, HNC, and C,N,H2 losses, and details of the reaction pathways are presented. The H atom loss was found to be due both to direct N-H bond cleavage and isomerization to form an azepine derivative.

Why Do Large Ionized Polycyclic Aromatic Hydrocarbons Not Lose C2H2?

The reaction mechanisms for the loss of C2H2 from the ions of anthracene, phenanthrene, tetracene, and pyrene were calculated at the B3-LYP/6-311++G(2d,p) level of theory and compared to that previously published for ionized naphthalene. A common pathway emerged involving the isomerization of the molecular ions to azulene-containing analogues, followed by the contraction of the seven-member ring into a five- and four-member fused ring system, leading to the cleavage of C2H2. The key transition state was found to be for this last process, and its relative energy was consistent going from naphthalene to tetracene. That for pyrene, though, was significantly higher due to the inability of the azulene moiety to achieve a stable conformation because of the presence of the three fused rings. Thus, C2H2 loss is discriminated against in pericondensed PAHs. For catacondensed PAHs, C2H2 loss also drops in relative abundance as the PAH gets larger due to the increase in the number of available hydrogen atoms, increasing the rate constant for H atom loss over that for C2H2 loss as PAH size increases. The unimolecular reactions of four cyano-substituted polycyclic aromatic hydrocarbon (PAH) ions were also probed as a function of collision energy by collision-induced dissociation tandem mass spectrometry. As the size of the ring system increases, HCN loss decreases in importance relative to other processes (H and C2H2 loss). 9-Cyanophenanthrene ions were chosen for further exploration by theory and imaging photoelectron photoion coincidence (iPEPICO) spectroscopy. The calculated reaction pathway and energetics for C2H2 loss were consistent with those found above. The calculations suggest that larger PAHs of interest in the interstellar environment will behave independently of a CN substituent.

The effects of ambient temperature and lighting intensity on wheel-running behavior in a diurnal rodent, the Nile grass rat (Arvicanthis niloticus).

Environmental conditions, such as the light-dark cycle and temperature, affect the display of circadian rhythmicity and locomotor activity patterns in mammals. Here, we tested the hypothesis that manipulating these environmental conditions would affect wheel-running activity patterns in a diurnal rodent, the Nile grass rat (Arvicanthis niloticus). Grass rats are diurnal in the field, however, a subset switch from a day-active pattern to a night-active pattern of activity after the introduction of a running wheel. The mechanism of this chronotype switch remains largely unknown. In the present study, grass rats were presented with running wheels in 12:12 light-dark conditions. First, subjects were exposed to 25 °C during the day and 21 °C at night, which resulted in 100% of grass rats expressing diurnal behavior. Subjects were then exposed to manipulations of elevated ambient temperature, which resulted in a significant reduction in wheel-running activity. Reducing ambient temperature below 21 °C, however, did not disrupt the expression of diurnality or overall activity. Next, lighting intensity was reduced, which resulted in a switch from a diurnal to a nocturnal chronotype in a subset of animals and reduced overall wheel-running activity. Upon return to baseline lighting intensity, patterns of diurnal activity were restored. Altogether, increases in ambient temperature and decreases in lighting intensity significantly reduced overall wheel-running activity. Importantly, dim light resulted in a temporal niche switch in a subset of grass rats, suggesting a critical role for lighting intensity on the expression of wheel-running activity patterns. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Purification and characterization of ribosomal proteins L27 and L30 having antimicrobial activity produced by the Lactobacillus salivarius SGL 03.

AIMS: The aim of this study was to investigate the antimicrobial potential of proteins secreted by a new strain of Lactobacillus salivarius. METHODS AND RESULTS: The secretome of L. salivarius SGL 03 strain was analysed by gel-assisted fractionation and MS/MS to identify low-molecular-mass proteins. This strategy allowed us to identify 10 secreted proteins. Then, a combination of heterologous expression and agar well diffusion was used to characterize them as to their antimicrobial activity, mechanisms of action and stability. Our findings indicate that L27 and L30 proteins of the 50S ribosomal subunit have antimicrobial activity against Streptococcus pyogenes, Streptococcus uberis and Enterococcus faecium. In addition, both proteins are bactericidal against S. pyogenes and maintain their antimicrobial activity after different protease treatments, at acidic pH, after heat treatment, and if stored in a refrigerated ambient at least at 4°C. CONCLUSIONS: The overall results demonstrated that the L27 and L30 ribosomal proteins are of interest as new antimicrobial molecules to prevent the growth of S. pyogenes, S. uberis and E. faecium. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide the first insight into the extra-ribosomal activity of L27 and L30 secreted proteins of L. salivarius. This study demonstrated the capacity of L. salivarius SGL 03 to produce antimicrobial molecules and suggested this strain as a promising probiotic candidate.

Preparedness Education in the Baccalaureate Nursing Curriculum: An Authentic Clinical Experience.

Healthy People 2020 supports the preparation of nurse graduates to assess emergency preparedness needs of defined populations and includes preparedness as one of its objectives. Natural disaster preparedness is addressed through the lens of community-centered care that meets the Quality and Safety Education for Nurses domains of patient-centered care and teamwork and collaboration. This article discusses the development of an authentic clinical experience through collaboration between the American Red Cross and a baccalaureate nursing program.

Draft Genome Sequence of Marine Sponge Symbiont Pseudoalteromonas luteoviolacea IPB1, Isolated from Hilo, Hawaii.

We report here the 6.0-Mb draft genome assembly of Pseudoalteromonas luteoviolacea strain IPB1 that was isolated from the Hawaiian marine sponge Iotrochota protea Genome mining complemented with bioassay studies will elucidate secondary metabolite biosynthetic pathways and will help explain the ecological interaction between host sponge and microorganism.

Inhibition of System Xc(-) Transporter Attenuates Autoimmune Inflammatory Demyelination.

T cell infiltration into the CNS is a significant underlying pathogenesis in autoimmune inflammatory demyelinating diseases. Several lines of evidence suggest that glutamate dysregulation in the CNS is an important consequence of immune cell infiltration in neuroinflammatory demyelinating diseases; yet, the causal link between inflammation and glutamate dysregulation is not well understood. A major source of glutamate release during oxidative stress is the system Xc(-) transporter; however, this mechanism has not been tested in animal models of autoimmune inflammatory demyelination. We find that pharmacological and genetic inhibition of system Xc(-) attenuates chronic and relapsing-remitting experimental autoimmune encephalomyelitis (EAE). Remarkably, pharmacological blockade of system Xc(-) 7 d after induction of EAE attenuated T cell infiltration into the CNS, but not T cell activation in the periphery. Mice harboring a Slc7a11 (xCT) mutation that inactivated system Xc(-) were resistant to EAE, corroborating a central role for system Xc(-) in mediating immune cell infiltration. We next examined the role of the system Xc(-) transporter in the CNS after immune cell infiltration. Pharmacological inhibitors of the system Xc(-) transporter administered during the first relapse in a SJL animal model of relapsing-remitting EAE abrogated clinical disease, inflammation, and myelin loss. Primary coculture studies demonstrate that myelin-specific CD4(+) Th1 cells provoke microglia to release glutamate via the system Xc(-) transporter, causing excitotoxic death to mature myelin-producing oligodendrocytes. Taken together, these studies support a novel role for the system Xc(-) transporter in mediating T cell infiltration into the CNS as well as promoting myelin destruction after immune cell infiltration in EAE.

Expression of Interferon-γ Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans.

OBJECTIVE: The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA. METHODS: In the first phase of the study, we performed real-time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (≤2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration. RESULTS: We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [P(adj)] = 6 × 10(-14)) and in IFNGR2 expression between RA patients with erosions and those with no erosions (P(adj) = 0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (P(adj) = 0.03 for erosions, P(adj) = 0.04 for joint space narrowing, and P(adj) = 0.03 for total radiographic score [zero-inflated negative binomial regression model]) and annualized progression rate (P(adj) = 0.0024 by Spearman's correlation analysis). CONCLUSION: These findings have important implications with respect to the role of interferon-γ (IFNγ) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFNγ receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations.

Evaluation of anti-HBV drug resistant mutations among patients with acute symptomatic hepatitis B in the United States.

BACKGROUND & AIMS: Reported HBV drug resistance mutations among previously untreated patients with chronic hepatitis B are variable. Whether resistant HBV strains are transmitted in the acute setting is uncertain. We sought to document the presence of antiviral resistance (AVR) mutations in patients with acute HBV (AHB) infection. METHODS: AHB infection was defined by HBsAg/IgM anti-HBc positivity, ALT>10X ULN and compatible clinical history. The TRUGENE HBV kit was used to perform genotyping and direct sequencing of the viral polymerase. INNO-LiPA HBV DRv2 and DRv3 were used to detect AVR mutations. Clonal sequencing was conducted on selected specimens. RESULTS: Twenty-three patients were evaluated (mean age, 43 years; 54% male; 39% African American, 39% Caucasian, 13% Hispanic and 4% Asian). The mean peak ALT was 1554.2IU/L and mean peak total serum bilirubin was 12 mg/dl. The HBV DNA median viral load (N = 15) was 5.14 log(10)IU/ml. Nineteen patients were genotype A, and 1 each were genotype C, D, E and G. HBV drug resistance mutations were not detected by direct sequencing or INNO-LiPA. Clonal sequencing was conducted on 192 clones isolated from three patients and showed rtA181T, rtM250V and rtS202G mutations at an overall frequency of 1.54%, 1.39%, and 1.67% respectively. CONCLUSIONS: We detected adefovir/lamivudine and entecavir relevant mutations in a minor population (<2%) of viral clones by clonal sequencing only. The clinical significance of these mutations is uncertain and may represent small populations of quasi-species vs. transmission of drug resistant strains.

Functional brain network changes associated with maintenance of cognitive function in multiple sclerosis.

In multiple sclerosis (MS) functional changes in connectivity due to cortical reorganization could lead to cognitive impairment (CI), or reflect a re-adjustment to reduce the clinical effects of widespread tissue damage. Such alterations in connectivity could result in changes in neural activation as assayed by executive function tasks. We examined cognitive function in MS patients with mild to moderate CI and age-matched controls. We evaluated brain activity using functional magnetic resonance imaging (fMRI) during the successful performance of the Wisconsin card sorting (WCS) task by MS patients, showing compensatory maintenance of normal function, as measured by response latency and error rate. To assess changes in functional connectivity throughout the brain, we performed a global functional brain network analysis by computing voxel-by-voxel correlations on the fMRI time series data and carrying out a hierarchical cluster analysis. We found that during the WCS task there is a significant reduction in the number of smaller size brain functional networks, and a change in the brain areas representing the nodes of these networks in MS patients compared to age-matched controls. There is also a concomitant increase in the strength of functional connections between brain loci separated at intermediate-scale distances in these patients. These functional alterations might reflect compensatory neuroplastic reorganization underlying maintenance of relatively normal cognitive function in the face of white matter lesions and cortical atrophy produced by MS.

IL-27 inhibits OSM-mediated TNF-alpha and iNOS gene expression in microglia.

Elevated levels of Oncostatin M (OSM), an interleukin-6 family cytokine, have been observed in multiple sclerosis (MS), HIV-associated neurocognitive disorder (HAND), and glioblastoma (GBM); however, its effects within the CNS are not well understood. OSM regulates gene expression primarily by activating the JAK/STAT, NF-kappaB, and/or MAPK pathways, in a cell-type specific manner. In our studies, OSM induces the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS) from microglia in an NF-kappaB-dependent manner. This expression also partially requires the intermediate production of TNF-alpha and subsequent NF-kappaB activation via TNF-R1. We also demonstrate that OSM-induced TNF-alpha production from microglia is neurotoxic. The IL-12 family member, IL-27, suppresses OSM-mediated TNF-alpha and iNOS expression at the transcriptional level by inhibiting activation of the NF-kappaB pathway, and rescues the neurotoxicity induced by OSM-stimulated microglia. These studies are the first to demonstrate the proinflammatory effects of OSM in microglia, and also identify IL-27 as a novel inhibitor of inflammatory processes in these cells.

IL-17 enhancement of the IL-6 signaling cascade in astrocytes.

Astrocytes have important physiological roles in CNS homeostasis and serve as a bridge between the CNS and immune system. IL-17 and IL-6 are important in many CNS disorders characterized by neuroinflammation. We examined the role of IL-17 on the IL-6 signaling cascade in primary astrocytes. IL-17 functioned in a synergistic manner with IL-6 to induce IL-6 expression in astrocytes. The synergistic effect involved numerous signaling pathways including NF-kappaB, JNK MAPK, and p38 MAPK. The NF-kappaB pathway inhibitor BAY-11, JNK inhibitor JNKi II, and p38 inhibitor SB203580 suppressed the synergistic effect of IL-6 and IL-17 on IL-6 expression. IL-17 synergized with IL-6 to enhance the recruitment of activated NF-kappaB p65, c-Fos, c-Jun, and the histone acetyltransferases CREB-binding protein and p300 to the IL-6 promoter in vivo to induce IL-6 transcription. This was accompanied by enhanced acetylation of histones H3 and H4 on the IL-6 promoter. Moreover, we elucidated an important role for suppressor of cytokine signaling (SOCS) 3 in IL-17 enhancement of IL-6 signaling in astrocytes. SOCS3 small interfering RNA knockdown and SOCS3 deletion in astrocytes augmented the synergistic effect of IL-6 and IL-17 due to an enhancement of activation of the NF-kappaB and MAPK pathways. These results indicate that astrocytes can serve as a target of Th17 cells and IL-17 in the CNS, and SOCS3 participates in IL-17 functions in the CNS as a negative feedback regulator.