Chapter One - STAT signaling in the intestine

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Abstract

The Janus kinase (JAK), signal transducer of activation (STAT) pathway, discovered by investigating interferon gene induction, is now recognized as an evolutionary conserved signaling pathway employed by diverse cytokines, interferons, growth factors, and related molecules. Since its discovery, this pathway has become a paradigm for membrane-to-nucleus signaling and explains how a broad range of soluble factors such as cytokines and hormones, mediate their diverse functions. The understanding of JAK-STAT signaling in the intestine has not only impacted basic science research, particularly in the understanding of intercellular communication and cell-extrinsic control of gene expression, but it has also become a prototype for transition of bench to bedside research, culminating in the clinical implementation of pathway-specific therapeutics.

Introduction

The human intestine is constantly exposed to antigens both from external sources (food, medications, etc.) as well as native stimuli (bacteria). The mucosal barrier ensures adequate containment of undesirable luminal contents within the intestine while preserving the ability to absorb nutrients. Barrier integrity is multifactorial and includes contributions from both the adaptive and the innate immune system (Aaronson and Horvath, 2002). A central signaling pathway in mucosal immunity is the JAK-STAT pathway, which regulate the adaptive and innate immune arms of mucosal immunity as well as epithelial repair and regeneration. Effective communication between cells is central to development, tissue and organism homeostasis, and host defense. Evolution has provided a number of elegant solutions to this problem, but among these the JAK-STAT pathway is one of the architecturally simplest paradigms, allowing direct communication from transmembrane receptors to the nucleus (Bergstrom et al., 2010).

The JAK-STAT pathway was first discovered in the early 1990s by Darnell and Stark. These investigators studied IFN activation of genes involved in immunity and identified STAT1 and STAT2. The JAK-STAT pathway is now recognized as one of the most important pleiotropic cascades employed by cells to transduce signals for hormones, growth factors, and cytokines (Harwig et al., 1995). This pathway contains the Janus kinase (JAK) proteins JAK1, JAK2, JAK3, and TYK2 and the signal transducer activators of transcription (STAT) proteins, STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. The JAK-STAT pathway provides the principle intracellular signaling mechanism required for a wide array of cytokines, including IL-2, IL-3, IL-4, IL-6, IL-7, IL-9, IL-11, IL-13, IL-15, IFN-γ and others. In addition to affecting cytokine responses, the JAK-STAT pathway also effects chemokines, hormones and growth factors, making it critical in cell development, cell growth and survival as well as vital implication in immune functions such as differentiation of T-helper lymphocyte cells.

Upon engagement by a ligand, receptor associated JAKs become activated and phosphorylate both each other and the intracellular tail of their receptors, thereby creating docking sites for latent, cytoplasmic transcription factors—STATs. JAK-mediated phosphorylation activates STATs, which in turn directly bind DNA and regulate gene expression (Fig. 1). The selective usage of JAKs by different receptors explains their distinct in vivo roles and is of great importance when generating pharmacologic inhibitors for specific disease states.

In mammals, four JAKs (JAK1, JAK2, JAK3, TYK2) and seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6) are used by > 50 cytokines and growth factors, raising the question of how specificity is achieved with so few building blocks. One explanation is that specificity is lineage dependent, meaning that cytokines that activate the same STATs may operate on different cell types (or states), each with distinct panels of STAT-sensitive genes. However, this does not explain why cytokines that “look” similar in terms of STAT signaling cascades can have different outcomes within the same cell type or state. This heterogeneity in signaling in the pathway may contribute to cytokine specificity and specific immune functions. Cytokine signaling cascades within immune cells are limited, and so the mechanism used to deliver complex signals remains elusive. Heterodimerization of STAT proteins is one potential mechanism for signals to be modified downstream of the receptor and may play an important role in dictating the targets of specific cytokine signaling. While over 50 cytokines have been implicated in playing distinct roles in immune cell function, there are only seven STAT molecules with which to transmit these signals.

It seems that many cytokines with distinct (and sometimes opposing) functions would activate the same STAT protein. For instance, IL-6, a proinflammatory cytokine that utilizes gp 130, promotes the activation of STAT3. IL-10, however, does not utilize gp130, is a potent anti-inflammatory cytokine, but also promotes the activation of STAT3. As the mechanism of STAT activation was better understood, the idea of post-translational modifications and their roles in the STAT signaling become more prominent. Modifications include phosphorylation, arginine methylation, acetylation, and ubiquitylation (although the physiologic relevance of the latter two has yet to be elucidated) (Delgoffe and Vignali, 2013). These modifications play a critical role in dimerization and certain aspects of cell signaling, with STAT dimers having distinct transcriptional targets compared to the phosphorylated counterparts (Guzzo et al., 2010).

The mechanism by which receptors promote STAT heterodimerization vs homodimerization is still elusive, although three mechanisms have been suggested. First, post-translational modification (PTM) of STATs induces the formation of a heterodimer or prevents the formation of a homodimer. Second, the structure of the individual cytokine receptors promotes the generation of STAT heterodimers, independent of PTM or other signaling pathways. Third, given that most cytokine receptors are composed of two or more distinct subunits, it may also be that differing subunits can recruit and activate distinct STAT proteins, and that mere proximity can promote the formation of a heterodimer. This complex heterodimer formation likely allows for heterogeneity in the STAT signaling response seen in the mucosal tissue.

The JAK-STAT pathway is critical for meeting the diverse challenges faced by the immune system, from resisting infection to maintaining immune tolerance, enforcing barrier functions, and guarding against cancer (Rawlings et al., 2004). However, this capacity comes at a steep price. Errant immune responses can inflict great harm, and not surprisingly, exaggerated or protracted JAK-STAT signaling has been implicated in just about every type of autoimmune disease. Therefore, a delicate balance must be reached to allow for both efficient induction of the JAK-STAT pathway when the immune system is called to action and proper diminution when the instigating threat subsides (Reich and Liu, 2006).

Section snippets

Mechanisms of JAK-STAT signaling in inflammatory bowel diseases (IBD)

JAK-STAT signaling pathways contribute to a range of cell processes including proliferation or apoptosis, migration, differentiation of immune cells, and development and differentiation of epithelial cells. The four mammalian JAKs are JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2). Binding of ligands—cytokines, or other small molecules such as interferons (IFN) or granulocyte-colony stimulating factor (G-CSF)—to extracellular receptors leads to auto- and trans-phosphorylation of JAKs and

JAK-STAT inhibition in the treatment of IBD

JAK-STAT inhibition is an area of active interest in the treatment of UC and CD and provides the foundation for a growing pharmacological class. Therapeutic inhibition of these pathways aims to reduce pro-inflammatory T cell activity and cytokine release and promote anti-inflammatory Treg activity. Potential drug targets may exist anywhere along the JAK-STAT pathway, including interference with cytokine binding to JAK receptors, blocking JAK receptors directly with antibodies or small molecule

Graft-versus-host disease

Allogeneic hematopoietic transplantation is commonly used to treat hematopoietic malignancies. The procedure requires chemoradiotherapy to neutralize much of the recipient's hematopoietic tissues before transplanting donor bone marrow. In a successful hematopoietic transplantation, the donor T-cells effect an immune response against the malignant tissues and clear the malignancy. Unsurprisingly, hematopoietic transplantation can have severe off-target effects, wherein the donor T-cells act

Infection

Although specific mechanisms of JAK/STAT signaling have not been shown to be therapeutic targets in intestinal infection, overall signaling through this pathway is responsible for cytokine dependent cell activation, secretion and transport of secretory IgA across the intestinal epithelium, and maintenance of the epithelial barrier.

TLR-mediated innate immune responses to PAMPs in the intestine trigger an array of cytokine responses (Feng et al., 2019; Heneghan et al., 2013; Zhang et al., 2019).

Cancer

The significant role of JAK/STAT signaling in cancer growth and tumorigenesis has long been recognized and investigated in the literature, with a particular focus on JAK2, STAT3, and STAT5 (O'Shea et al., 2015; Spano et al., 2006). JAK2 hyperactivity, by means of gain-of-function mutations or autocrine/paracrine cytokine signaling, accelerates proliferation and can lead to malignancy through this proliferative dysregulation (Lu et al., 2017; O'Shea et al., 2015).

Contrastingly, the IFN-mediated

Conclusion

JAK-STAT signaling is one of the principal signaling pathways utilized by cytokine receptors. Since the discovery of this pathway, many studies elucidated the role of this pathway in many processes including cell development, growth and survival. The several roles of JAK-STAT signaling in the mucosal immune response to bacteria, viruses, and other antigens have elucidated important roles for JAK-STAT signaling in T cell differentiation, B cell maturation and development, secretion of sIgA, and

References (89)

  • J. Mishra et al.

    Role of Janus kinase 3 in mucosal differentiation and predisposition to colitis

    J. Biol. Chem.

    (2013)
  • J. Rengarajan et al.

    Transcriptional regulation of Th1/Th2 polarization

    Immunol. Today

    (2000)
  • W.J. Sandborn et al.

    Safety of Tofacitinib for treatment of ulcerative colitis, based on 4.4 years of data from global clinical trials

    Clin. Gastroenterol. Hepatol.

    (2019)
  • C. Soendergaard et al.

    Targeting JAK-STAT signal transduction in IBD

    Pharmacol. Ther.

    (2018)
  • J.-P. Spano et al.

    JAK/STAT signalling pathway in colorectal cancer: a new biological target with therapeutic implications

    Eur. J. Cancer

    (2006)
  • G.L. Stritesky et al.

    The transcription factor STAT3 is required for T helper 2 cell development

    Immunity

    (2011)
  • T. Teshima et al.

    Acute graft-versus-host disease: novel biological insights

    Biol. Blood Marrow Transplant.

    (2016)
  • S. Vermeire et al.

    Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial

    Lancet

    (2017)
  • C. Vogtenhuber et al.

    Constitutively active Stat5b in CD4 + T cells inhibits graft-versus-host disease lethality associated with increased regulatory T-cell potency and decreased T effector cell responses

    Blood

    (2010)
  • D.S. Aaronson et al.

    A road map for those who don’t know JAK-STAT

    Science

    (2002)
  • R. Abboud et al.

    Insights into the role of the JAK/STAT signaling pathway in graft-versus-host disease

    Ther. Adv. Hematol.

    (2020)
  • I. Arijs et al.

    Mucosal gene expression of antimicrobial peptides in inflammatory bowel disease before and after first infliximab treatment

    PLoS One

    (2009)
  • R. Atreya et al.

    Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: evidence in crohn disease and experimental colitis in vivo

    Nat. Med.

    (2000)
  • A. Bai et al.

    Blockade of STAT3 by antisense oligonucleotide in TNBS-induced murine colitis

    Int. J. Colorectal Dis.

    (2007)
  • S. Banerjee et al.

    JAK-STAT signaling as a target for inflammatory and autoimmune diseases: current and future prospects

    Drugs

    (2017)
  • J.C. Barrett et al.

    Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

    Nat. Genet.

    (2008)
  • K.S. Bergstrom et al.

    Muc2 protects against lethal infectious colitis by disassociating pathogenic and commensal bacteria from the colonic mucosa

    PLoS Pathog.

    (2010)
  • S. Brand

    Crohn's disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn's disease

    Gut

    (2009)
  • S.B. Cohen et al.

    Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials

    Ann. Rheum. Dis.

    (2017)
  • A.P. Costa-Pereira et al.

    Mutational switch of an IL-6 response to an interferon-gamma-like response

    Proc. Natl. Acad. Sci. U. S. A.

    (2002)
  • G.M. Delgoffe et al.

    STAT heterodimers in immunity: a mixed message or a unique signal?

    JAKSTAT

    (2013)
  • L. Feng et al.

    Seselin ameliorates inflammation via targeting Jak2 to suppress the proinflammatory phenotype of macrophages

    Br. J. Pharmacol.

    (2019)
  • I.J. Fuss et al.

    Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis

    J. Clin. Invest.

    (2004)
  • S. Gilbert et al.

    Enterocyte STAT5 promotes mucosal wound healing via suppression of myosin light chain kinase-mediated loss of barrier function and inflammation

    EMBO Mol. Med.

    (2012)
  • J. Han et al.

    Stat3: friend or foe in colitis and colitis-associated cancer?

    Inflamm. Bowel Dis.

    (2014)
  • S.N. Harbour et al.

    Th17 cells give rise to Th1 cells that are required for the pathogenesis of colitis

    Proc. Natl. Acad. Sci. U. S. A.

    (2015)
  • S.S. Harwig et al.

    Bactericidal properties of murine intestinal phospholipase A2

    J. Clin. Invest.

    (1995)
  • M. Hedl et al.

    JAK2 disease-risk variants are gain of function and JAK signaling threshold determines innate receptor-induced proinflammatory cytokine secretion in macrophages

    J. Immunol.

    (2016)
  • A.F. Heneghan et al.

    JAK-STAT and intestinal mucosal immunology

    JAKSTAT

    (2013)
  • Y.-Q. Hong et al.

    Macrophage regulation of graft-vs-host disease

    World J. Clin. Cases

    (2020)
  • P. Hruz et al.

    STAT3 and its activators in intestinal defense and mucosal homeostasis

    Curr. Opin. Gastroenterol.

    (2010)
  • K. Ji et al.

    The role of p-STAT3 as a prognostic and clinicopathological marker in colorectal cancer: a systematic review and meta-analysis

    PLoS One

    (2016)
  • H. Jia et al.

    Therapeutic effects of STAT3 inhibition by nifuroxazide on murine acute graft graft-vs.-host disease: old drug, new use

    Mol. Med. Rep.

    (2017)
  • S.Z. Josefowicz et al.

    Regulatory T cells: mechanisms of differentiation and function

    Annu. Rev. Immunol.

    (2012)
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      Citation Excerpt :

      It is widely accepted that the inflammation observed in this disease is induced by immune cells and accompanying production of pro-inflammatory cytokines and reactive oxygen species. Particular cell-signaling pathways play key roles in supporting immune cell activity in this process including the Janus kinase-signal transducer of activation (JAK-STAT) pathway, which is critical for the differentiation of naïve T cells into T effector cells (Nobel, Stier, & Krishnareddy, 2021; Simpson et al., 1998). In addition to these immune cell-intrinsic effects, other factors can influence the pathogenesis of disease.

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