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1.  Unifying roles for regulatory T cells and inflammation in cancer 
Activities of CD4+ regulatory (TREG) cells restore immune homeostasis during chronic inflammatory disorders. Roles for TREG cells in inflammation-associated cancers, however, are paradoxical. It is widely believed that TREG function in cancer mainly to suppress protective anticancer responses. However, we demonstrate here that TREG cells also function to reduce cancer risk throughout the body by efficiently downregulating inflammation arising from the gastrointestinal (GI) tract. Building on a “hygiene hypothesis” model in which GI infections lead to changes in TREG that reduce immune-mediated diseases, here we show that gut bacteria-triggered TREG may function to inhibit cancer even in extraintestinal sites. Ability of bacteria-stimulated TREG to suppress cancer depends on interleukin (IL)-10, which serves to maintain immune homeostasis within bowel and support a protective antiinflammatory TREG phenotype. However, under proinflammatory conditions, TREG may fail to provide antiinflammatory protection and instead contribute to a T helper (Th)-17-driven procarcinogenic process; a cancer state that is reversible by downregulation of inflammation. Consequently, hygienic individuals with a weakened IL-10 and TREG-mediated inhibitory loop are highly susceptible to the carcinogenic consequences of elevated IL-6 and IL-17 and show more frequent inflammation-associated cancers. Taken together, these data unify seemingly divergent disease processes such as autoimmunity and cancer and help explain the paradox of TREG and inflammation in cancer. Enhancing protective TREG functions may promote healthful longevity and significantly reduce risk of cancer.
doi:10.1002/ijc.24923
PMCID: PMC4068029  PMID: 19795459
gut bacteria; regulatory T cells; IL-6; IL-17; colon cancer; breast cancer
2.  TNF receptor 2 induces IRF1 transcription factor-dependent interferon-β autocrine signaling to promote monocyte recruitment 
Immunity  2013;38(5):1025-1037.
SUMMARY
Endothelial-dependent mechanisms of mononuclear cell influx are not well understood. We showed that acute stimulation of murine microvascular endothelial cells expressing the receptors TNFR1 and TNFR2 with the soluble cytokine TNF, led to CXCR3 chemokine generation. The TNF receptors signaled through Interferon regulatory factor-1 (IRF1) to induce interferon-β (IFN-β) and subsequent autocrine signaling via the type I IFN receptor and the transcription factor STAT1. Both TNFR2 and TNFR1 were required for IRF1-IFNβ signaling and, in human endothelial cells TNFR2 expression alone induced IFN-β signaling and monocyte recruitment. In vivo, TNFR1 was required for acute renal neutrophil and monocyte influx after systemic TNF treatment, whereas the TNFR2-IRF1-IFN-β autocrine loop was essential only for macrophage accumulation. In a chronic model of proliferative nephritis, IRF1 and renal expressed TNFR2, were essential for sustained macrophage accumulation. Thus, our data identify a pathway in endothelial cells that selectively recruits monocytes during a TNF-induced inflammatory response.
doi:10.1016/j.immuni.2013.01.012
PMCID: PMC3760474  PMID: 23623383
3.  Wiskott-Aldrich Syndrome Protein Deficiency in Innate Immune Cells Leads to Mucosal Immune Dysregulation and Colitis in Mice 
Gastroenterology  2012;143(3):719-29.e1-2.
Background & Aims
Immunodeficiency and autoimmune sequelae, including colitis, develop in patients and mice deficient in Wiskott-Aldrich Syndrome protein (WASP), a hematopoietic-specific intracellular signaling molecule that regulates the actin cytoskeleton. Development of colitis in WASP-deficient mice requires lymphocytes; transfer of T cells is sufficient to induce colitis in immunodeficient mice. We investigated the interactions between innate and adaptive immune cells in mucosal regulation during development of T-cell-mediated colitis in mice with WASP-deficient cells of the innate immune system.
Methods
Naïve and/or regulatory CD4+ T cells were transferred from 129 SvEv mice into RAG-2 deficient (RAG-2 KO) mice or mice lacking WASP and RAG-2 (WRDKO). Animals were observed for the development of colitis; effector and regulatory functions of innate immune and T cells were analyzed with in vivo and in vitro assays.
Results
Transfer of unfractionated CD4+ T cells induced severe colitis in WRDKO, but not RAG-2 KO, mice. Naïve wild-type T cells had higher levels of effector activity and regulatory T cells had reduced suppressive function when transferred into WRDKO mice compared to RAG-2 KO mice. Regulatory T-cell proliferation, generation, and maintenance of FoxP3 expression were reduced in WRDKO recipients, and associated with reduced numbers of CD103+ tolerogenic dendritic cells and levels of interleukin (IL)-10. Administration of IL-10 prevented induction of colitis following transfer of T cells into WRDKO mice.
Conclusions
Defective interactions between WASP-deficient innate immune cells and normal T cells disrupt mucosal regulation, potentially by altering the functions of tolerogenic dendritic cells, production of IL-10, and homeostasis of regulatory T cells.
doi:10.1053/j.gastro.2012.06.008
PMCID: PMC3760724  PMID: 22710191
antigen presenting cells; inflammatory bowel disease; mouse model; immunodeficiency
4.  Pathogenic Intestinal Bacteria Enhance Prostate Cancer Development via Systemic Activation of Immune Cells in Mice 
PLoS ONE  2013;8(8):e73933.
A role for microbes has been suspected in prostate cancer but difficult to confirm in human patients. We show here that a gastrointestinal (GI) tract bacterial infection is sufficient to enhance prostate intraepithelial neoplasia (PIN) and microinvasive carcinoma in a mouse model. We found that animals with a genetic predilection for dysregulation of wnt signaling, ApcMin/+ mutant mice, were significantly susceptible to prostate cancer in an inflammation-dependent manner following infection with Helicobacter hepaticus. Further, early neoplasia observed in infected ApcMin/+ mice was transmissible to uninfected mice by intraperitoneal injection of mesenteric lymph node (MLN) cells alone from H. hepaticus-infected mutant mice. Transmissibility of neoplasia was preventable by prior neutralization of inflammation using anti-TNF-α antibody in infected MLN donor mice. Taken together, these data confirm that systemic inflammation triggered by GI tract bacteria plays a pivotal role in tumorigenesis of the prostate gland.
doi:10.1371/journal.pone.0073933
PMCID: PMC3753256  PMID: 23991210
5.  Nfkb1 Inhibits LPS-Induced IFN-β and IL-12 p40 Production in Macrophages by Distinct Mechanisms 
PLoS ONE  2012;7(3):e32811.
Background
Nfkb1-deficient murine macrophages express higher levels of IFN-β and IL-12 p40 following LPS stimulation than control macrophages, but the molecular basis for this phenomenon has not been completely defined. Nfkb1 encodes several gene products including the NF-κB subunit p50 and its precursor p105. p50 is derived from the N-terminal of 105, and p50 homodimers can exhibit suppressive activity when overexpressed. The C-terminal region of p105 is necessary for LPS-induced ERK activation and it has been suggested that ERK activity inhibits both IFN-β and IL-12 p40 following LPS stimulation. However, the contributions of p50 and the C-terminal domain of p105 in regulating endogenous IFN-β(Ifnb) and IL-12 p40 (Il12b) gene expression in macrophages following LPS stimulation have not been directly compared.
Methodology/Principal Findings
We have used recombinant retroviruses to express p105, p50, and the C-terminal domain of p105 (p105ΔN) in Nfkb1-deficient murine bone marrow-derived macrophages at near endogenous levels. We found that both p50 and p105ΔN inhibited expression of Ifnb, and that inhibition of Ifnb by p105ΔN depended on ERK activation, because a mutant of p105ΔN (p105ΔNS930A) that lacks a key serine necessary to support ERK activation failed to inhibit. In contrast, only p105ΔN but not p50 inhibited Il12b expression. Surprisingly, p105ΔNS930A retained inhibitory activity for Il12b, indicating that ERK activation was not necessary for inhibition. The differential effects of p105ΔNS930A on Ifnb and Il12b expression inversely correlated with the function of one of its binding partners, c-Rel. This raised the possibility that p105ΔNS930A influences gene expression by interfering with the function of c-Rel.
Conclusions
These results demonstrate that Nfkb1 exhibits multiple gene-specific inhibitory functions following TLR stimulation of murine macrophages.
doi:10.1371/journal.pone.0032811
PMCID: PMC3299705  PMID: 22427889
6.  NF-κB1 Inhibits TLR-Induced IFN-β Production in Macrophages Through TPL-2-dependent ERK Activation1 
Although NF-κB1 p50/p105 has critical roles in immunity, the mechanism by which NF-κB1 regulates inflammatory responses is unclear. Here, we analyzed the gene expression profile of lipopolysaccharide (LPS)-stimulated Nfkb1−/− macrophages that lack both p50 and p105. Deficiency of p50/p105 selectively increased the expression of interferon (IFN)-responsive genes, which correlated with increased IFN-β expression and STAT1 phosphorylation. Interferon antibody blocking experiments indicated that increased STAT1 phosphorylation and expression of interferon-responsive genes observed in the absence of p50/p105 depended upon autocrine IFN-β production. Markedly higher serum levels of IFN-β were observed in Nfkb1−/− mice than in WT mice following LPS injection demonstrating that Nfkb1 inhibits IFN-β production under physiological conditions. TPL-2, a mitogen-activated protein kinase kinase kinase stabilized by association with the C-terminal ankyrin repeat domain of p105, negatively regulates LPS-induced interferon-β production by macrophages via activation of ERK MAP kinase. Retroviral expression of TPL-2 in Nfkb1−/− macrophages, which are deficient in endogenous TPL-2, reduced LPS-induced interferon-β secretion. Expression of the C-terminal ankyrin repeat domain of p105 in Nfkb1−/− macrophages, which rescued LPS activation of ERK also inhibited IFN-β expression. These data indicate that p50/p105 negatively regulates LPS induced interferon-signaling in macrophages by stabilizing TPL-2, thereby facilitating activation of ERK.
doi:10.4049/jimmunol.1001003
PMCID: PMC3070925  PMID: 21217011
8.  c-Rel is Essential for the Development of Innate and T cell-Induced Colitis1 
Inflammatory bowel disease is a chronic inflammatory response of the gastrointestinal tract mediated in part by an aberrant response to intestinal microflora. Expression of IL-23 subunits p40 and p19 within cells of the innate immune system plays a central role in the development of lower bowel inflammation in response inflammatory challenge. The NF-κB subunit c-Rel can regulate expression of IL-12/23 subunits suggesting that it could have a critical role in mediating the development of chronic inflammation within the lower bowel. Here we have analyzed the role of c-Rel within the innate immune system in the development of lower bowel inflammation, in two well-studied models of murine colitis. We have found that the absence of c-Rel significantly impaired the ability of H. hepaticus to induce colitis upon infection of RAG-2-deficient mice, and ameliorated the ability of CD4+CD45RBhigh T cells to induce disease upon adoptive transfer into RAG-deficient mice. The absence of c-Rel interfered with the expression of IL-12/23 subunits both in cultured primary macrophages and within the colon. Thus, c-Rel plays a critical role in regulating the innate inflammatory response to microflora within the lower bowel, likely through its ability to modulate expression of IL-12/23 family members.
PMCID: PMC2585753  PMID: 18523276
Rodent; Transcription Factors; Inflammation; Macrophages; Mucosa
9.  Cytotoxic-T-Lymphocyte-Associated Antigen 4 Blockade Abrogates Protection by Regulatory T Cells in a Mouse Model of Microbially Induced Innate Immune-Driven Colitis▿  
Infection and Immunity  2008;76(12):5834-5842.
Cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4) expressed at high levels by CD4+ CD25+ CD45RBlow regulatory T cells (Treg) is essential to their homeostatic and immunoregulatory functions. However, its relevance to anti-inflammatory roles of Treg in the context of colitogenic innate immune response during pathogenic bacterial infections has not been examined. We showed earlier in Rag2-deficient 129/SvEv mice that Treg cells are capable of suppressing colitis and colon cancer triggered by Helicobacter hepaticus, a widespread murine enterohepatic pathogen. Using this model, we now examined the effects of antibody blockade of CTLA-4 on Treg function during innate immune inflammatory response. Consistent with our previous findings, we found that a single adoptive transfer of Treg cells prior to infection prevented colitis development despite persistent H. hepaticus infection in recipient mice. However, when infected mice were injected with anti-CTLA-4 antibody along with Treg cell transfer, they developed a severe acute colitis with poor body condition that was not observed in Rag2−/− mice without Treg cell transfer. Despite high numbers of Foxp3+ Treg cells, evident by immunohistochemical analyses in situ, the CTLA-4 antibody-treated mice had severely inflamed colonic mucosa and increased rather than decreased expression levels of cytokines gamma interferon and interleukin-2. These findings indicate that antibody blockade of CTLA-4 clearly abrogates Treg cell ability to suppress innate immune-driven colitis and suggest that Treg cell CTLA-4 cognate interactions may be necessary to maintain homeostasis among cells of innate immunity.
doi:10.1128/IAI.00542-08
PMCID: PMC2583565  PMID: 18824539
10.  Gastroenteritis in NF-κB-Deficient Mice Is Produced with Wild-Type Camplyobacter jejuni but Not with C. jejuni Lacking Cytolethal Distending Toxin despite Persistent Colonization with Both Strains  
Infection and Immunity  2004;72(2):1116-1125.
Campylobacter jejuni continues to be a leading cause of bacterial enteritis in humans. However, because there are no readily available animal models to study the pathogenesis of C. jejuni-related diseases, the significance of potential virulence factors, such as cytolethal distending toxin (CDT), in vivo are poorly understood. Mice deficient in NF-κB subunits (p50−/− p65+/−) in a C57BL/129 background are particularly susceptible to colitis induced by another enterohepatic microaerobe, Helicobacter hepaticus, which, like C. jejuni, produces CDT. Wild-type C. jejuni 81-176 and an isogenic mutant lacking CDT activity (cdtB mutant) were inoculated into NF-κB-deficient (3X) and C57BL/129 mice. Wild-type C. jejuni colonized 29 and 50% of the C57BL/129 mice at 2 and 4 months postinfection (p.i.), respectively, whereas the C. jejuni cdtB mutant colonized 50% of the C57BL/129 mice at 2 p.i. but none of the mice at 4 months p.i. Although the C57BL/129 mice developed mild gastritis and typhlocolitis, they had robust immunoglobulin G (IgG) and Th1-promoted IgG2a humoral responses to both the wild-type strain and the C. jejuni cdtB mutant. In contrast, 75 to 100% of the 3X mice were colonized with both the wild type and the C. jejuni cdtB mutant at similar levels at all times examined. Wild-type C. jejuni caused moderately severe gastritis and proximal duodenitis in 3X mice that were more severe than the gastrointestinal lesions caused by the C. jejuni cdtB mutant. Persistent colonization of NF-κB-deficient mice with the wild type and the C. jejuni cdtB mutant was associated with significantly impaired IgG and IgG2a humoral responses (P < 0.001), which is consistent with an innate or adaptive immune system defect(s). These results suggest that the mechanism of clearance of C. jejuni is NF-κB dependent and that CDT may have proinflammatory activity in vivo, as well as a potential role in the ability of C. jejuni to escape immune surveillance. NF-κB-deficient mice should be a useful model to further study the role of CDT and other aspects of C. jejuni pathogenesis.
doi:10.1128/IAI.72.2.1116-1125.2004
PMCID: PMC321575  PMID: 14742559
11.  Nuclear Factor κb Is Required for the Development of Marginal Zone B Lymphocytes 
The Journal of Experimental Medicine  2000;192(8):1175-1182.
Although immunoglobulin (Ig)MhiIgDlo/−CD21hi marginal zone B cells represent a significant proportion of naive peripheral splenic B lymphocytes, few of the genes that regulate their development have been identified. This subset of peripheral B cells fails to emerge in mice that lack nuclear factor (NF)-κBp50. Less drastic reductions in marginal zone B cell numbers are also seen in the spleens of recombination activating gene (Rag)-2−/− mice reconstituted with NF-κBp65−/− fetal liver cells and in c-Rel−/− mice. In contrast, steady-state levels of IgDhi splenic follicular B cells are not significantly reduced in the absence of NF-κBp50, NF-κBp65, or c-Rel. Reconstitution of B cells in Rag-2−/− mice with a mixture of p50−/−/p65−/− fetal liver cells and Rag-2−/− bone marrow cells revealed that the generation of marginal zone B cells requires the expression of NF-κB in developing B cells, as opposed to supporting cells.
PMCID: PMC2195875  PMID: 11034607
transcription factors; lymphocyte development; recombination activating gene-2−/− mice; peripheral B cells; Bruton's tyrosine kinase

Results 1-11 (11)