The predominantly anaerobic microbiota of the distal ileum and colon contain an extraordinarily complex variety of metabolically active bacteria and fungi that intimately interact with the host's epithelial cells and mucosal immune system. Crohn's disease, ulcerative colitis, and pouchitis are the result of continuous microbial antigenic stimulation of pathogenic immune responses as a consequence of host genetic defects in mucosal barrier function, innate bacterial killing, or immunoregulation. Altered microbial composition and function in inflammatory bowel diseases result in increased immune stimulation, epithelial dysfunction, or enhanced mucosal permeability. Although traditional pathogens probably are not responsible for these disorders, increased virulence of commensal bacterial species, particularly Escherichia coli, enhance their mucosal attachment, invasion, and intracellular persistence, thereby stimulating pathogenic immune responses. Host genetic polymorphisms most likely interact with functional bacterial changes to stimulate aggressive immune responses that lead to chronic tissue injury. Identification of these host and microbial alterations in individual patients should lead to selective targeted interventions that correct underlying abnormalities and induce sustained and predictable therapeutic responses.

T helper (T(H)) cells constitute an important arm of the adaptive immune system because they coordinate defence against specific pathogens, and their unique cytokines and effector functions mediate different types of tissue inflammation. The recently discovered T(H)17 cells, the third subset of effector T helper cells, have been the subject of intense research aimed at understanding their role in immunity and disease. Here we review emerging data suggesting that T(H)17 cells have an important role in host defence against specific pathogens and are potent inducers of autoimmunity and tissue inflammation. In addition, the differentiation factors responsible for their generation have revealed an interesting reciprocal relationship with regulatory T (T(reg)) cells, which prevent tissue inflammation and mediate self-tolerance.

Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel disorders. In this paper, we discuss how environmental factors (eg, geography, cigarette smoking, sanitation and hygiene), infectious microbes, ethnic origin, genetic susceptibility, and a dysregulated immune system can result in mucosal inflammation. After describing the symbiotic interaction of the commensal microbiota with the host, oral tolerance, epithelial barrier function, antigen recognition, and immunoregulation by the innate and adaptive immune system, we examine the initiating and perpetuating events of mucosal inflammation. We pay special attention to pattern-recognition receptors, such as toll-like receptors and nucleotide-binding-oligomerisation-domains (NOD), NOD-like receptors and their mutual interaction on epithelial cells and antigen-presenting cells. We also discuss the important role of dendritic cells in directing tolerance and immunity by modulation of subpopulations of effector T cells, regulatory T cells, Th17 cells, natural killer T cells, natural killer cells, and monocyte-macrophages in mucosal inflammation. Implications for novel therapies, which are discussed in detail in the second paper in this Series, are covered briefly.

T helper type 1 (T(H)1) cell development involves interferon-gamma (IFN-gamma) signaling through signal transducer and activator of transcription 1 (STAT1) and interleukin-12 (IL-12) signaling through STAT4 activation. We examined here T-bet regulation and evaluated the actions of T-bet in STAT1- and STAT4-dependent T(H)1 development processes. We found that T-bet expression during T cell activation was strongly dependent on IFN-gamma signaling and STAT1 activation, but was independent of STAT4. Ectopic T-bet expression strongly increased IFN-gamma production in T(H)2 cells activated by PMA-ionomycin, but weakly increased IFN-gamma production in T(H)2 cells stimulated by IL-12 IL-18 or OVA peptide antigen-presenting cell stimulation. In contrast, IL-12 IL-18 induced IFN-gamma production remained STAT4-dependent despite ectopic T-bet expression. Ectopic T-bet expression selectively induced expression of IL-12Rbeta2, but not IL-18Ralpha, in wild-type and STAT1(-/-) T(H)2 cells, but did not extinguish expression of GATA-3 and T(H)2 cytokines. Finally, ectopic T-bet did not directly induce expression of endogenous T- bet independently of IFN-gamma or STAT1. Thus, T-bet is induced by IFN-gamma and STAT1 signaling during T cell activation. In addition, T-bet mediates STAT1-dependent processes of T(H)1 development, including the induction of IL-12Rbeta2.

The NOD (nucleotide-binding oligomerization domain) proteins NOD1 and NOD2 have important roles in innate immunity as sensors of microbial components derived from bacterial peptidoglycan. The importance of these molecules is underscored by the fact that mutations in the gene that encodes NOD2 occur in a subpopulation of patients with Crohn's disease, and NOD1 has also been shown to participate in host defence against infection with Helicobacter pylori. Here, we focus on the molecular interactions between these NOD proteins and other intracellular molecules to elucidate the mechanisms by which NOD1 and NOD2 contribute to the maintenance of mucosal homeostasis and the induction of mucosal inflammation.

Abnormal production of inflammatory mediators is believed to play an important role in the pathogenesis of psoriasis. Emerging data, both in mice and in humans, put the spotlight on a new subset of T helper (Th) cells, in part characterized by their production of IL-17 and accordingly named Th17 cells. Here, we review the development, characterization, and function of human Th17 cells as well as the crucial role of IL-23 in the context of Th17-cell-dependent chronic inflammation in psoriasis. We further discuss recent clinical trials targeting the IL-23/Th17 axis in psoriasis.

The last few years have witnessed a rapid increase in our knowledge of the retinoid-related orphan receptors RORalpha, -beta, and -gamma (NR1F1-3), their mechanism of action, physiological functions, and their potential role in several pathologies. The characterization of ROR-deficient mice and gene expression profiling in particular have provided great insights into the critical functions of RORs in the regulation of a variety of physiological processes. These studies revealed that RORalpha plays a critical role in the development of the cerebellum, that both RORalpha and RORbeta are required for the maturation of photoreceptors in the retina, and that RORgamma is essential for the development of several secondary lymphoid tissues, including lymph nodes. RORs have been further implicated in the regulation of various metabolic pathways, energy homeostasis, and thymopoiesis. Recent studies identified a critical role for RORgamma in lineage specification of uncommitted CD4+ T helper cells into Th17 cells. In addition, RORs regulate the expression of several components of the circadian clock and may play a role in integrating the circadian clock and the rhythmic pattern of expression of downstream (metabolic) genes. Study of ROR target genes has provided insights into the mechanisms by which RORs control these processes. Moreover, several reports have presented evidence for a potential role of RORs in several pathologies, including osteoporosis, several autoimmune diseases, asthma, cancer, and obesity, and raised the possibility that RORs may serve as potential targets for chemotherapeutic intervention. This prospect was strengthened by recent evidence showing that RORs can function as ligand-dependent transcription factors.

IL-18 is a product of macrophages and with IL-12 strikingly induces IFN-gamma production from T, B, and NK cells. Furthermore, IL-18 and 1L-12 synergize for IFN-gamma production from Th1 cells, although this combination fails to affect Th2 cells. In this study, we show that IL-12 and IL-18 promptly and synergistically induce T and B cells to develop into IFN-gamma-producing cells without engaging their Ag receptors. We also studied the mechanism underlying differences in IL-18 responsiveness between Th1 and Th2 cells. Pretreatment of T or B cells with IL-12 rendered them responsive to IL-18, which induces cell proliferation and IFN-gamma production. These IL-12-stimulated cells had both high and low affinity IL-18R and an increased IL-18R mRNA expression. In particular, IL-12-stimulated T cells strongly and continuously expressed IL-18R mRNA. However, when T cells developed into Th1 cells after stimulation with anti-CD3 and IL-12, they lowered this IL-12-induced-IL-18R mRNA expression. Then, such T cells showed a dominant response to anti-CD3 by IFN-gamma production when they were subsequently stimulated with anti-CD3 and IL-18. In contrast, Th2 cells did not express IL-18R mRNA and failed to produce IFN-gamma in response to anti-CD3 and IL-18, although they produced a substantial amount of IFN-gamma in response to anti-CD3 and IL-12. However, when Th1 and Th2 cells were stimulated with anti-CD3, IL-12, and IL-18, only the Th1 cells markedly augmented IFN-gamma production in response to IL-18, suggesting that IL-18 responsiveness between Th1 and Th2 cells resulted from their differential expression of IL-18R.

The paradigm of effector T helper cell differentiation into either Th1 or Th2 lineages has been profoundly shaken by the discovery of T cells that secrete IL-17 and other inflammatory cytokines. This subset, referred to as Th17, is centrally involved in autoimmune disease and is important in host defense at mucosal surfaces. In mouse, a series of cytokines, including IL-6, IL-21, IL-23, and TGF-beta, function sequentially or synergistically to induce the Th17 lineage. Other cytokines, including IL-2, IL-4, IFNgamma, and IL-27, inhibit differentiation of this lineage. Here we review how the nuclear orphan receptor RORgammat functions to coordinate the diverse cytokine-induced signals and thus controls Th17 cell differentiation.

Mucosal immunity relies on the delicate balance between antigen responsiveness and tolerance. The polarization of T helper cells plays a key role in maintaining or disrupting this equilibrium.

The differentiation of naive CD4+ T cells into subsets of T helper cells is a pivotal process with major implications for host defense and the pathogenesis of immune-mediated diseases. Though the basic paradigm was discovered more than 15 years ago, new discoveries continue to be made that offer fresh insights into the regulation of this process. T helper (TH)1 cells produce interferon (IFN)-gamma, promoting cell-mediated immunity and control of intracellular pathogens. We now know that TH1 differentiation is regulated by transcription factors such as T-bet, Stat1, and Stat4, as well as cytokines such as IL-12, IL-23, IL-27, type I IFNs, and IFN-gamma. In contrast, TH2 cells produce IL-4, which promotes allergic responses and is important in host defense against helminths. The transcription factors Stat6, GATA-3, c-Maf, NFATs, and the cytokine IL-4 promote TH2 differentiation. These key regulators of TH differentiation are the subject of this review.

Crohn's disease and ulcerative colitis are chronic relapsing immune mediated disorders that results from an aberrant response to gut luminal antigen in genetically susceptible host. The adaptive immune response that is then triggered was widely considered to be a T-helper-1 mediated condition in Crohn's disease and T-helper-2 mediated condition in ulcerative colitis. Recent studies in animal models, genome wide association, and basic science has provided important insights in in the immunopathogenesis of inflammatory bowel disease, one of which was the characterization of the interleukin-23/Th-17 axis.

Inflammatory bowel disease (IBD) is a group of idiopathic, chronic and relapsing inflammatory conditions of the gastrointestinal tract. Familial and epidemiological studies have stressed the involvement of genetic factors and have also shown the critical role of environmental factors such as sanitation and hygiene in the development of IBD. However, the molecular mechanisms of intestinal inflammation in IBD have long remained unknown. In recent years, the study of susceptibility genes involved in the detection of bacterial components and in the regulation of the host immune response has shed light onto the potential role of intestinal pathogens and gut flora in IBD immunobiology. This review presents current knowledge on intestinal epithelial barrier alterations and on dysfunction of mucosal innate and acquired immune responses in IBD. The data support the etiological hypothesis which argues that pathogenic intestinal bacteria and/or infectious agents initiate and perpetuate the inflammation of the gut through disruption of tolerance towards the commensal microbiota in an individual with genetic vulnerability.

The treatment of patients with IBD has evolved towards biologic therapy, which seeks to target specific immune and biochemical abnormalities at the molecular and cellular level. Multiple genes have been associated with susceptibility to IBD, and many of these can be linked to alterations in immune pathways. These immune pathways provide avenues for understanding the pathogenesis of IBD and suggest future drug targets, such as the IL-12-IL-23 pathway. In addition, failed therapeutic drug trials can provide valuable information about pitfalls in study design, drug delivery and disease activity assessment. Future biologic drug development will benefit from the early identification of subsets of patients who are most likely to respond to therapy by use of biological markers of genetic susceptibility or immunologic susceptibility.

The purpose of this review is to provide an overview of the effects that natural products have on inflammatory bowel disease (IBD) and to provide insight into the relationship between these natural products and cytokines modulation. More than 100 studies from the past 10 years were reviewed herein on the therapeutic approaches for treating IBD. The natural products having anti-IBD actions included phytochemicals, antioxidants, microorganisms, dietary fibers, and lipids. The literature revealed that many of these natural products exert anti-IBD activity by altering cytokine production. Specifically, phytochemicals such as polyphenols or flavonoids are the most abundant, naturally occurring anti-IBD substances. The anti-IBD effects of lipids were primarily related to the n-3 polyunsaturated fatty acids. The anti-IBD effects of phytochemicals were associated with modulating the levels of tumor necrosis factor α (TNF-α), interleukin (IL)-1, IL-6, inducible nitric oxide synthase, and myeloperoxide. The anti-IBD effects of dietary fiber were mainly mediated via peroxisome proliferator-activated receptor-γ, TNF-α, nitric oxide, and IL-2, whereas the anti-IBD effects of lactic acid bacteria were reported to influence interferon-γ, IL-6, IL-12, TNF-α, and nuclear factor-κ light-chain enhancer of activated B cells. These results suggest that the anti-IBD effects exhibited by natural products are mainly caused by their ability to modulate cytokine production. However, the exact mechanism of action of natural products for IBD therapy is still unclear. Thus, future research is needed to examine the effect of these natural products on IBD and to determine which factors are most strongly correlated with reducing IBD or controlling the symptoms of IBD.

The factors involved in the pathogenesis of Crohn's disease and ulcerative colitis, the two major types of inflammatory bowel disease (IBD) are summarized. Intestinal antigens composed of bacterial flora along with antigen presentation and impaired mucosal barrier have an important role in the initiation of IBD. The bacterial community may be modified by the use of antibiotics and probiotics. The dentritic cells recognize the antigens by cell surface Toll like receptor and the cytoplasmic CARD/NOD system. The balance between Th1/Th2/Th17 cell populations being the source of a variety of cytokines regulates the inflammatory mechanisms and the clearance of microbes. The intracellular killing and digestion, including autophagy, are important in the protection against microbes and their toxins. The homing process determines the location and distribution of the immune cells along the gut. All these players are potential targets of pharmacological manipulation of disease status.