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1.
PLoS Pathog ; 20(7): e1012302, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38949991

ABSTRACT

Oropharyngeal candidiasis (OPC) is the most common human fungal infection, arising typically from T cell immune impairments. IL-17 and IL-22 contribute individually to OPC responses, but here we demonstrate that the combined actions of both cytokines are essential for resistance to OPC. Mice lacking IL-17RA and IL-22RA1 exhibited high fungal loads in esophagus- and intestinal tract, severe weight loss, and symptoms of colitis. Ultimately, mice succumbed to infection. Dual loss of IL-17RA and IL-22RA impaired expression of small proline rich proteins (SPRRs), a class of antimicrobial effectors not previously linked to fungal immunity. Sprr2a1 exhibited direct candidacidal activity in vitro, and Sprr1-3a-/- mice were susceptible to OPC. Thus, cooperative actions of Type 17 cytokines mediate oral mucosal anti-Candida defenses and reveal a role for SPRRs.


Subject(s)
Candidiasis, Oral , Interleukin-17 , Interleukin-22 , Interleukins , Mice, Knockout , Animals , Mice , Candida albicans/immunology , Candidiasis, Oral/immunology , Candidiasis, Oral/microbiology , Interleukin-17/immunology , Interleukin-17/metabolism , Interleukins/immunology , Interleukins/metabolism , Mice, Inbred C57BL , Receptors, Interleukin/immunology , Receptors, Interleukin/metabolism , Receptors, Interleukin-17/immunology , Receptors, Interleukin-17/metabolism
3.
JCI Insight ; 7(18)2022 09 22.
Article in English | MEDLINE | ID: mdl-36134659

ABSTRACT

A side effect of antibiotics is outgrowth of the opportunistic fungus Candida albicans in the oropharynx (oropharyngeal candidiasis, OPC). IL-17 signaling is vital for immunity to OPC, but how the microbiome impacts antifungal immunity is not well understood. Mice in standard specific pathogen-free (SPF) conditions are resistant to OPC, whereas we show that germ-free (GF) or antibiotic-treated mice are susceptible. Oral type 17 cells and IL-17-dependent responses were impaired in antibiotic-treated and GF mice. Susceptibility could be rescued in GF mice by mono-colonization with segmented filamentous bacterium (SFB), an intestine-specific constituent of the microbiota. SFB protection was accompanied by restoration of oral IL-17+CD4+ T cells and gene signatures characteristic of IL-17 signaling. Additionally, RNA-Seq revealed induction of genes in the retinoic acid (RA) and RA receptor-α (RARα) pathway. Administration of RA rescued immunity to OPC in microbiome-depleted or GF mice, while RAR inhibition caused susceptibility in immunocompetent animals. Surprisingly, immunity to OPC was independent of serum amyloids. Moreover, RAR inhibition did not alter oral type 17 cytokine levels. Thus, mono-colonization with a component of the intestinal microflora confers protection against OPC by type 17 and RA/RARα, which act in parallel to promote antifungal immunity. In principle, manipulation of the microbiome could be harnessed to maintain antifungal immunity.


Subject(s)
Candidiasis, Oral , Gastrointestinal Microbiome , Animals , Anti-Bacterial Agents , Antifungal Agents/pharmacology , Candidiasis, Oral/microbiology , Interleukin-17/metabolism , Mice , Mouth Mucosa/microbiology , Tretinoin
4.
Sci Immunol ; 6(61)2021 07 02.
Article in English | MEDLINE | ID: mdl-34215679

ABSTRACT

Excessive cytokine activity underlies many autoimmune conditions, particularly through the interleukin-17 (IL-17) and tumor necrosis factor-α (TNFα) signaling axis. Both cytokines activate nuclear factor κB, but appropriate induction of downstream effector genes requires coordinated activation of other transcription factors, notably, CCAAT/enhancer binding proteins (C/EBPs). Here, we demonstrate the unexpected involvement of a posttranscriptional "epitranscriptomic" mRNA modification [N6-methyladenosine (m6A)] in regulating C/EBPß and C/EBPδ in response to IL-17A, as well as IL-17F and TNFα. Prompted by the observation that C/EBPß/δ-encoding transcripts contain m6A consensus sites, we show that Cebpd and Cebpb mRNAs are subject to m6A modification. Induction of C/EBPs is enhanced by an m6A methylase "writer" and suppressed by a demethylase "eraser." The only m6A "reader" found to be involved in this pathway was IGF2BP2 (IMP2), and IMP2 occupancy of Cebpd and Cebpb mRNA was enhanced by m6A modification. IMP2 facilitated IL-17-mediated Cebpd mRNA stabilization and promoted translation of C/EBPß/δ in response to IL-17A, IL-17F, and TNFα. RNA sequencing revealed transcriptome-wide IL-17-induced transcripts that are IMP2 influenced, and RNA immunoprecipitation sequencing identified the subset of mRNAs that are directly occupied by IMP2, which included Cebpb and Cebpd Lipocalin-2 (Lcn2), a hallmark of autoimmune kidney injury, was strongly dependent on IL-17, IMP2, and C/EBPß/δ. Imp2-/- mice were resistant to autoantibody-induced glomerulonephritis (AGN), showing impaired renal expression of C/EBPs and Lcn2 Moreover, IMP2 deletion initiated only after AGN onset ameliorated disease. Thus, posttranscriptional regulation of C/EBPs through m6A/IMP2 represents a previously unidentified paradigm of cytokine-driven autoimmune inflammation.


Subject(s)
Adenosine/analogs & derivatives , CCAAT-Enhancer-Binding Proteins/immunology , Interleukin-17/immunology , RNA-Binding Proteins/immunology , Tumor Necrosis Factor-alpha/immunology , Adenosine/immunology , Animals , Autoimmunity/immunology , CCAAT-Enhancer-Binding Proteins/genetics , Cell Line , Female , Humans , Inflammation/immunology , Interleukin-17/genetics , Male , Mice, Inbred C57BL , Mice, Knockout , RNA-Binding Proteins/genetics
5.
mBio ; 13(1): e0379221, 2021 02 22.
Article in English | MEDLINE | ID: mdl-35100872

ABSTRACT

Excessive inflammation can cause tissue damage and autoimmunity, sometimes accompanied by severe morbidity or mortality. Numerous negative feedback mechanisms exist to prevent unchecked inflammation, but this restraint may come at the cost of suboptimal infection control. Regnase-1 (MCPIP1), a feedback regulator of IL-17 and LPS signaling, binds and degrades target mRNAs. Consequently, Reg1 deficiency exacerbates autoimmunity in multiple models. However, the role of Reg1 in bacterial immunity remains poorly defined. Here, we show that mice deficient in Reg1 are resistant to Klebsiella pneumoniae (KP). Reg1 deficiency did not accelerate bacterial eradication. Rather, Reg1-deficient alveolar macrophages had elevated Ifnb1 and enrichment of type I IFN genes. Blockade of IFNR during KP infection reversed disease improvement. Reg1 did not impact Ifnb1 stability directly, but Irf7 expression was affected. Thus, Reg1 suppresses type I IFN signaling restricting resistance to KP, suggesting that Reg1 could potentially be a target in severe bacterial infections. IMPORTANCE Klebsiella pneumoniae (KP) can cause life-threatening bacterial pneumonia and is the third most common cause of ventilator-associated pneumonia in the United States. Host inflammatory responses to infection are necessary to control disease, yet at the same time can cause collateral damage or immunopathology. During immune responses, many events are established within the infected tissue to limit unchecked inflammation. However, this restraint of immunity can impair infection control, and it is not fully understood how this balance is maintained during different infection settings. In this study we explored the possibility that a host-derived negative regulator of RNA, Regnase-1, limits immunity to KP by dampening inflammation. Indeed, mice with reduced Regnase-1 levels showed improved survival to KP infection, linked to regulation of type I interferons. Therefore, although restraint of Reg1 is beneficial to prevent immunopathology, temporary blockade of Reg1 could potentially be exploited to improve host defense during infectious settings such as KP.


Subject(s)
Interferon Type I , Klebsiella Infections , Pneumonia, Bacterial , Animals , Mice , Klebsiella pneumoniae , Pneumonia, Bacterial/microbiology , Endoribonucleases , Inflammation , Klebsiella Infections/microbiology , Lithostathine
6.
J Immunol ; 205(3): 720-730, 2020 08 01.
Article in English | MEDLINE | ID: mdl-32601099

ABSTRACT

Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the commensal fungus Candida albicans IL-17R signaling is essential to prevent OPC in mice and humans, but the individual roles of its ligands, IL-17A, IL-17F, and IL-17AF, are less clear. A homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of IL-17F and IL-17AF in more detail, we exploited this "experiment of nature" by creating a mouse line bearing the homologous mutation in IL-17F (Ser65Leu) by CRISPR/Cas9. Unlike Il17f-/- mice that are resistant to OPC, Il17fS65L/S65L mice showed increased oral fungal burdens similar to Il17a -/- mice. In contrast to humans, however, disease was only evident in homozygous, not heterozygous, mutant mice. The mutation was linked to modestly impaired CXC chemokine expression and neutrophil recruitment to the infected tongue but not to alterations in oral antimicrobial peptide expression. These findings suggest mechanisms by which the enigmatic cytokine IL-17F contributes to host defense against fungi. Moreover, because these mice do not phenocopy Il17f-/- mice, they may provide a valuable tool to interrogate IL-17F and IL-17AF function in vivo in other settings.


Subject(s)
Candida albicans/immunology , Candidiasis/immunology , Interleukin-17/immunology , Mouth Diseases/immunology , Animals , Candida albicans/genetics , Candidiasis/genetics , Candidiasis/pathology , Gene Knock-In Techniques , Interleukin-17/genetics , Mice , Mice, Transgenic , Mouth Diseases/genetics , Mouth Diseases/microbiology , Mouth Diseases/pathology , Mutation, Missense
7.
Sci Immunol ; 5(48)2020 06 05.
Article in English | MEDLINE | ID: mdl-32503875

ABSTRACT

Oropharyngeal candidiasis (OPC; thrush) is an opportunistic infection caused by the commensal fungus Candida albicans Interleukin-17 (IL-17) and IL-22 are cytokines produced by type 17 lymphocytes. Both cytokines mediate antifungal immunity yet activate quite distinct downstream signaling pathways. While much is now understood about how IL-17 promotes immunity in OPC, the activities of IL-22 are far less well delineated. We show that, despite having similar requirements for induction from type 17 cells, IL-22 and IL-17 function nonredundantly during OPC. We find that the IL-22 and IL-17 receptors are required in anatomically distinct locations within the oral mucosa; loss of IL-22RA1 or signal transducer and activator of transcription 3 (STAT3) in the oral basal epithelial layer (BEL) causes susceptibility to OPC, whereas IL-17RA is needed in the suprabasal epithelial layer (SEL). Transcriptional profiling of the tongue linked IL-22/STAT3 not only to oral epithelial cell proliferation and survival but also, unexpectedly, to driving an IL-17-specific gene signature. We show that IL-22 mediates regenerative signals on the BEL that replenish the IL-17RA-expressing SEL, thereby restoring the ability of the oral epithelium to respond to IL-17 and thus to mediate antifungal events. Consequently, IL-22 signaling in BEL "licenses" IL-17 signaling in the oral mucosa, revealing spatially distinct yet cooperative activities of IL-22 and IL-17 in oral candidiasis.


Subject(s)
Candidiasis, Oral/immunology , Epithelial Cells/immunology , Interleukin-17/immunology , Interleukins/immunology , Mouth Mucosa/immunology , STAT3 Transcription Factor/immunology , Animals , Candida albicans/immunology , Female , Interleukin-17/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Signal Transduction/immunology , Interleukin-22
8.
PLoS One ; 15(2): e0228177, 2020.
Article in English | MEDLINE | ID: mdl-32040522

ABSTRACT

BACKGROUND: Sterile protection against malaria, most likely mediated by parasite-specific CD8+ T cells, has been achieved by attenuated sporozoite vaccination of animals as well as malaria-naïve and malaria-exposed subjects. The circumsporozoite protein (CSP)-based vaccine, RTS,S, shows low efficacy partly due to limited CD8+ T cell induction, and inclusion of such epitopes could improve RTS,S. This study assessed 8-10mer CSP peptide epitopes, present in predicted or previously positive P. falciparum 3D7 CSP 15mer overlapping peptide pools, for their ability to induce CD8+ T cell IFN-γ responses in natural malaria-exposed subjects. METHODS: Cryopreserved PBMCs from nine HLA-typed subjects were stimulated with 23 8-10mer CSP peptides from the 3D7 parasite in IFN-É£ ELISpot assays. The CD8+ T cell specificity of IFN-γ responses was confirmed in ELISpot assays using CD8+ T cell-enriched PBMC fractions after CD4+ cell depletion. RESULTS: Ten of 23 peptide epitopes elicited responses in whole PBMCs from five of the nine subjects. Four peptides tested positive in CD8+ T cell-enriched PBMCs from two previously positive responders and one new subject. All four immunodominant peptides are restricted by globally common HLA supertypes (A02, A03, B07) and mapped to regions of the CSP antigen with limited or no reported polymorphism. Association of these peptide-specific responses with anti-malarial protection remains to be confirmed. CONCLUSIONS: The relatively conserved nature of the four identified epitopes and their binding to globally common HLA supertypes makes them good candidates for inclusion in potential multi-epitope malaria vaccines.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Epitopes, T-Lymphocyte/immunology , Malaria, Falciparum/prevention & control , Plasmodium falciparum/immunology , Protozoan Proteins/immunology , Amino Acid Sequence , CD8-Positive T-Lymphocytes/drug effects , Epitopes, T-Lymphocyte/chemistry , Epitopes, T-Lymphocyte/drug effects , Interferon-gamma/pharmacology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology
9.
J Infect Dis ; 221(9): 1554-1563, 2020 04 07.
Article in English | MEDLINE | ID: mdl-31805183

ABSTRACT

Candida albicans, a ubiquitous commensal fungus that colonizes human mucosal tissues and skin, can become pathogenic, clinically manifesting most commonly as oropharyngeal candidiasis and vulvovaginal candidiasis (VVC). Studies in mice and humans convincingly show that T-helper 17 (Th17)/interleukin 17 (IL-17)-driven immunity is essential to control oral and dermal candidiasis. However, the role of the IL-17 pathway during VVC remains controversial, with conflicting reports from human data and mouse models. Like others, we observed induction of a strong IL-17-related gene signature in the vagina during estrogen-dependent murine VVC. As estrogen increases susceptibility to vaginal colonization and resulting immunopathology, we asked whether estrogen use in the standard VVC model masks a role for the Th17/IL-17 axis. We demonstrate that mice lacking IL-17RA, Act1, or interleukin 22 showed no evidence for altered VVC susceptibility or immunopathology, regardless of estrogen administration. Hence, these data support the emerging consensus that Th17/IL-17 axis signaling is dispensable for the immunopathogenesis of VVC.


Subject(s)
Candidiasis, Vulvovaginal/immunology , Estrogens/administration & dosage , Interleukin-17/immunology , Receptors, Interleukin-17/immunology , Receptors, Interleukin/immunology , Animals , Candida albicans , Candidiasis, Oral/immunology , Candidiasis, Oral/pathology , Candidiasis, Vulvovaginal/pathology , Disease Models, Animal , Estrogens/metabolism , Female , Mice , Mice, Inbred C57BL , Mucous Membrane/pathology , Signal Transduction/immunology , Vagina/microbiology
10.
Infect Immun ; 87(11)2019 11.
Article in English | MEDLINE | ID: mdl-31451621

ABSTRACT

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia worldwide, and interleukin-22 (IL-22) helps contain pneumococcal burden in lungs and extrapulmonary tissues. Administration of IL-22 increases hepatic complement 3 and complement deposition on bacteria and improves phagocytosis by neutrophils. The effects of IL-22 can be tempered by a secreted natural antagonist, known as IL-22 binding protein (IL-22BP), encoded by Il22ra2 To date, the degree to which IL-22BP controls IL-22 in pulmonary infection is not well defined. Here, we show that Il22ra2 inhibits IL-22 during S. pneumoniae lung infection and that Il22ra2 deficiency favors downregulation of oxidative phosphorylation (OXPHOS) genes in an IL-22-dependent manner. Il22ra2-/- mice are more resistant to S. pneumoniae infection, have increased IL-22 in lung tissues, and sustain longer survival upon infection than control mice. Transcriptome sequencing (RNA-seq) analysis of infected Il22ra2-/- mouse lungs revealed downregulation of genes involved in OXPHOS. Downregulation of this metabolic process is necessary for increased glycolysis, a crucial step for transitioning to a proinflammatory phenotype, in particular macrophages and dendritic cells (DCs). Accordingly, we saw that macrophages from Il22ra2-/- mice displayed reduced OXPHOS gene expression upon infection with S. pneumoniae, changes that were IL-22 dependent. Furthermore, we showed that macrophages express IL-22 receptor subunit alpha-1 (IL-22Ra1) during pneumococcal infection and that Il22ra2-/- macrophages rely more on the glycolytic pathway than wild-type (WT) controls. Together, these data indicate that IL-22BP deficiency enhances IL-22 signaling in the lung, thus contributing to resistance to pneumococcal pneumonia by downregulating OXPHOS genes and increasing glycolysis in macrophages.


Subject(s)
Interleukins/metabolism , Pneumonia, Pneumococcal/metabolism , Receptors, Interleukin/metabolism , Animals , Cell Line , Disease Susceptibility , Epithelial Cells/physiology , Gene Expression Regulation , Interleukins/genetics , Leukocyte Common Antigens , Lung/cytology , Macrophages/metabolism , Mice , Mice, Knockout , Oxidation-Reduction , Phosphorylation , Pneumonia, Pneumococcal/immunology , Receptors, Interleukin/genetics , Streptococcus pneumoniae , Interleukin-22
11.
Sci Rep ; 9(1): 8621, 2019 06 13.
Article in English | MEDLINE | ID: mdl-31197225

ABSTRACT

The current global malaria control and elimination agenda requires development of additional effective disease intervention tools. Discovery and characterization of relevant parasite antigens is important for the development of new diagnostics and transmission monitoring tools and for subunit vaccine development. This study assessed the natural antibody response profile of seven novel Plasmodium falciparum pre-erythrocytic antigens and their potential association with protection against clinical malaria. Antigen-specific antibody levels in plasma collected at six time points from a longitudinal cohort of one-to-five year old children resident in a seasonal malaria transmission area of northern Ghana were assessed by ELISA. Antibody levels were compared between parasite-positive and parasite-negative individuals and the association of antibody levels with malaria risk assessed using a regression model. Plasma antibody levels against five of the seven antigens were significantly higher in parasite-positive children compared to parasite-negative children, especially during low transmission periods. None of the antigen-specific antibodies showed an association with protection against clinical malaria. The study identified five of the seven antigens as markers of exposure to malaria, and these will have relevance for the development of disease diagnostic and monitoring tools. The vaccine potential of these antigens requires further assessment.


Subject(s)
Antigens, Protozoan/immunology , Malaria, Falciparum/immunology , Malaria, Falciparum/parasitology , Plasmodium falciparum/immunology , Antibodies, Protozoan/immunology , Child, Preschool , Cohort Studies , Epitopes/immunology , Ghana , Humans , Infant , Linear Models , Longitudinal Studies , Parasitemia/immunology , Parasitemia/parasitology
12.
Trends Immunol ; 40(6): 469-471, 2019 06.
Article in English | MEDLINE | ID: mdl-31053496

ABSTRACT

A recent study shows that the commensal fungus Candida albicans is an inducer of differentiation of human CD4+ Th17 cells that harbor heterologous specificity for other fungi, which may explain evolutionary benefits of C. albicans as a commensal microbe (Bacher et al. Cell 2019;176;1340-1355). However, Th17 cells that are crossreactive to Aspergillus fumigatus antigens can also drive exaggerated airway inflammation in humans.


Subject(s)
Candida albicans , Th17 Cells , Cell Differentiation , Humans , Immunity , Inflammation
13.
Sci Signal ; 11(551)2018 10 09.
Article in English | MEDLINE | ID: mdl-30301788

ABSTRACT

Interleukin-17A (IL-17A) not only stimulates immunity to fungal pathogens but also contributes to autoimmune pathology. IL-17 is only a modest activator of transcription in experimental tissue culture settings. However, IL-17 controls posttranscriptional events that enhance the expression of target mRNAs. Here, we showed that the RNA binding protein (RBP) Arid5a (AT-rich interactive domain-containing protein 5a) integrated multiple IL-17-driven signaling pathways through posttranscriptional control of mRNA. IL-17 induced expression of Arid5a, which was recruited to the adaptor TRAF2. Arid5a stabilized IL-17-induced cytokine transcripts by binding to their 3' untranslated regions and also counteracted mRNA degradation mediated by the endoribonuclease MCPIP1 (Regnase-1). Arid5a inducibly associated with the eukaryotic translation initiation complex and facilitated the translation of the transcription factors (TFs) IκBζ (Nfkbiz ) and C/EBPß (Cebpb). These TFs in turn transactivated IL-17-dependent promoters. Together, these data indicated that Arid5a orchestrates a feed-forward amplification loop, which promoted IL-17 signaling by controlling mRNA stability and translation.


Subject(s)
DNA-Binding Proteins/metabolism , Interleukin-17/metabolism , Signal Transduction , Transcription Factors/metabolism , 3' Untranslated Regions , Adaptor Proteins, Signal Transducing/metabolism , Animals , CCAAT-Enhancer-Binding Protein-beta/metabolism , Cytokines/metabolism , Fibroblasts/metabolism , HEK293 Cells , Humans , Inflammation , Keratinocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Proteins/metabolism , Protein Binding , RNA, Messenger/metabolism , RNA-Binding Proteins/metabolism , Ribonucleases/metabolism , TNF Receptor-Associated Factor 2/metabolism
14.
J Immunol ; 201(2): 627-634, 2018 07 15.
Article in English | MEDLINE | ID: mdl-29891557

ABSTRACT

Protection against microbial infection by the induction of inflammation is a key function of the IL-1 superfamily, including both classical IL-1 and the new IL-36 cytokine families. Candida albicans is a frequent human fungal pathogen causing mucosal infections. Although the initiators and effectors important in protective host responses to C. albicans are well described, the key players in driving these responses remain poorly defined. Recent work has identified a central role played by IL-1 in inducing innate Type-17 immune responses to clear C. albicans infections. Despite this, lack of IL-1 signaling does not result in complete loss of immunity, indicating that there are other factors involved in mediating protection to this fungus. In this study, we identify IL-36 cytokines as a new player in these responses. We show that C. albicans infection of the oral mucosa induces the production of IL-36. As with IL-1α/ß, induction of epithelial IL-36 depends on the hypha-associated peptide toxin Candidalysin. Epithelial IL-36 gene expression requires p38-MAPK/c-Fos, NF-κB, and PI3K signaling and is regulated by the MAPK phosphatase MKP1. Oral candidiasis in IL-36R-/- mice shows increased fungal burdens and reduced IL-23 gene expression, indicating a key role played by IL-36 and IL-23 in innate protective responses to this fungus. Strikingly, we observed no impact on gene expression of IL-17 or IL-17-dependent genes, indicating that this protection occurs via an alternative pathway to IL-1-driven immunity. Thus, IL-1 and IL-36 represent parallel epithelial cell-driven protective pathways in immunity to oral C. albicans infection.


Subject(s)
Candida albicans/immunology , Candidiasis/immunology , Fungal Proteins/metabolism , Interleukin-17/metabolism , Interleukin-1/metabolism , Mouth Mucosa/physiology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Line , Gene Expression Regulation , Immunity, Innate , Interleukin-23/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mouth Mucosa/microbiology , Receptors, Interleukin-1/genetics , Signal Transduction , p38 Mitogen-Activated Protein Kinases/metabolism
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