Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies--the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.

Mitogen-activated protein kinases in innate immunity

The mammalian stress-activated families of mitogen-activated protein kinases (MAPKs) were first elucidated in 1994, and by 2001, substantial progress had been made in identifying the architecture of the pathways upstream of these kinases as well as in cataloguing candidate substrates. This information remains largely sound. Nevertheless, an informed understanding of the physiological and pathophysiological roles of these kinases remained to be accomplished. In the past decade, there has been an explosion of new work using RNAi in cells, as well as transgenic, knockout and conditional knockout technology in mice that has provided valuable insight into the functions of stress-activated MAPK pathways. These findings have important implications in our understanding of organ development, innate and acquired immunity, and diseases such as atherosclerosis, tumorigenesis, and type 2 diabetes. These new developments bring us within striking distance of the development and validation of novel treatment strategies. Herein we first summarize the molecular components of the mammalian stress-regulated MAPK pathways and their regulation as described thus far. We then review some of the in vivo functions of these pathways.

Mammalian MAPK Signal Transduction Pathways Activated by Stress and Inflammation: A 10-Year Update

Two members of the NF-κB (nuclear factor κB)/Rel transcription factor family, NF-κB1 and NF-κB2, are produced as precursor proteins, NF-κB1 p105 and NF-κB2 p100 respectively. These are proteolytically processed by the proteasome to produce the mature transcription factors NF-κB1 p50 and NF-κB2 p52. p105 and p100 are known to function additionally as IκBs (inhibitors of NF-κB), which retain associated NF-κB subunits in the cytoplasm of unstimulated cells. The present review focuses on the latest advances in research on the function of NF-κB1 and NF-κB2 in immune cells. NF-κB2 p100 processing has recently been shown to be stimulated by a subset of NF-κB inducers, including lymphotoxin-β, B-cell activating factor and CD40 ligand, via a novel signalling pathway. This promotes the nuclear translocation of p52-containing NF-κB dimers, which regulate peripheral lymphoid organogenesis and B-lymphocyte differentiation. Increased p100 processing also contributes to the malignant phenotype of certain T- and B-cell lymphomas. NF-κB1 has a distinct function from NF-κB2, and is important in controlling lymphocyte and macrophage function in immune and inflammatory responses. In contrast with p100, p105 is constitutively processed to p50. However, after stimulation with agonists, such as tumour necrosis factor-α and lipopolysaccharide, p105 is completely degraded by the proteasome. This releases associated p50, which translocates into the nucleus to modulate target gene expression. p105 degradation also liberates the p105-associated MAP kinase (mitogen-activated protein kinase) kinase kinase TPL-2 (tumour progression locus-2), which can then activate the ERK (extracellular-signal-regulated kinase)/MAP kinase cascade. Thus, in addition to its role in NF-κB activation, p105 functions as a regulator of MAP kinase signalling.

Functions of NF-κB1 and NF-κB2 in immune cell biology

Mouse models of inflammatory bowel disease.

Summary: There are now many experimental models of inflammatory bowel disease (IBD), most of which are due to induced mutations in mice that result in an impaired homeostasis with the intestinal microbiota. These models can be clustered into several broad categories that, in turn, define the crucial cellular and molecular mechanisms of host microbial interactions in the intestine. The first of these components is innate immunity defined broadly to include both myeloid and epithelial cell mechanisms. A second component is the effector response of the adaptive immune system, which, in most instances, comprises the CD4+ T cell and its relevant cytokines. The third component is regulation, which can involve multiple cell types, but again particularly involves CD4+ T cells. Severe impairment of a single component can result in disease, but many models demonstrate milder defects in more than one component. The same is true for both spontaneous models of IBD, C3H/HeJBir and SAMPI/Yit mice. The thesis is advanced that ‘multiple hits’ or defects in these interacting components is required for IBD to occur in both mouse and human.

Experimental Models of Inflammatory Bowel Disease Reveal Innate, Adaptive, and Regulatory Mechanisms of Host Dialogue With the Microbiota

Recent clinical evidence demonstrated the importance of tumor necrosis factor (TNF) in the development of Crohn's disease. A mouse model for this pathology has previously been established by engineering defects in the translational control of TNF mRNA (TnfΔAREmouse). Here, we show that development of intestinal pathology in this model depends on Th1-like cytokines such as interleukin 12 and interferon γ and requires the function of CD8+ T lymphocytes. Tissue-specific activation of the mutant TNF allele by Cre/loxP-mediated recombination indicated that either myeloid- or T cell–derived TNF can exhibit full pathogenic capacity. Moreover, reciprocal bone marrow transplantation experiments using TNF receptor–deficient mice revealed that TNF signals are equally pathogenic when directed independently to either bone marrow–derived or tissue stroma cell targets. Interestingly, TNF-mediated intestinal pathology was exacerbated in the absence of MAPKAP kinase 2, yet strongly attenuated in a Cot/Tpl2 or JNK2 kinase–deficient genetic background. Our data establish the existence of redundant cellular pathways operating downstream of TNF in inflammatory bowel disease, and demonstrate the therapeutic potential of selective kinase blockade in TNF-mediated intestinal pathology.

https://rupress.org/jem/article-pdf/196/12/1563/1140896/jem196121563.pdf

George Boulougouris

Papers

Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease.