Jin-Chul Kim

RIG-I RNA Helicase Activation of IRF3 Transcription Factor Is Negatively Regulated by Caspase-8-Mediated Cleavage of the RIP1 Protein

Excessive responses to pattern-recognition receptors are prevented by regulatory mechanisms that affect the amounts and activities of the downstream signaling proteins. We report that activation of the transcription factor IRF3 by the ribonucleic acid sensor RIG-I was restricted by caspase-8-mediated cleavage of the RIP1 protein, which resulted in conversion of RIP1 from a signaling enhancer to a signaling inhibitor. The proteins RIP1 and caspase-8 were recruited to the RIG-I complex after viral infection and served antagonistic regulatory roles. Conjugation of ubiquitin chains to RIP1 facilitated assembly of the RIG-I complex, resulting in enhanced phosphorylation of IRF3. However, the ubiquitination of RIP1 also rendered it susceptible to caspase-8-mediated cleavage that yielded an inhibitory RIP1 fragment. The dependence of RIP1 cleavage on the same molecular change as that facilitating RIG-I signaling allows for RIG-I signaling to be restricted in its duration without compromising its initial activation.

Role of caspase-8 in hepatocyte response to infection and injury in mice†

Caspase‐8 has been implicated in signaling for apoptotic cell death and for certain nonapoptotic functions. However, knowledge of actual physiological or pathophysiological processes to which this enzyme contributes is lacking. Using a mouse model and employing the conditional knockout approach to delete the caspase‐8 gene specifically in the liver, we found that caspase‐8 deficiency in hepatocytes facilitates infection of the liver by Listeria monocytogenes, attenuates the hepatocyte proliferation wave during the first 48 hours after partial hepatectomy and, depending on the genetic background of the mice, prompts a chronic inflammatory response to the hepatectomy, as a result of which the proliferation of hepatocytes, although initially suppressed, might later be persistently enhanced, resulting in significant hepatomegaly. Conclusion: These findings indicate that caspase‐8 participates in regulation of the cellular response to infection and injury and that it does so by affecting various cellular functions, including cell death, cell proliferation, and induction of inflammation. (HEPATOLOGY 2007.)

IL-17 drives psoriatic inflammation via distinct, target cell-specific mechanisms

Significance Psoriasis is an inflammatory disease affecting the skin, a barrier site. The disease is characterized by abnormal growth of keratinocytes and infiltration of inflammatory cells. Clinical trials targeting the IL-17 cytokine have shown remarkable efficacy, and IL-17 also has been strongly implicated in the imiquimod-induced mouse model of psoriasis. However why IL-17 cytokines should be so central is not known, because target cells and their functions have not been clearly delineated. Here we demonstrate that IL-17 signaling into nonkeratinocytes, specifically dermal fibroblasts, induces mediators that further increase IL-17 production by innate γδT cells and promote cellular infiltration, whereas IL-17 signaling into keratinocytes aids proliferation and blocks their differentiation. These findings reveal the circuitry underpinning critical disease-driving effects of IL-17. Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and differentiation and by an influx of inflammatory cells. The mechanisms underlying psoriasis in humans and in mouse models are poorly understood, although evidence strongly points to crucial contributions of IL-17 cytokines, which signal via the obligatory adaptor CIKS/Act1. Here we identify critical roles of CIKS/Act1-mediated signaling in imiquimod-induced psoriatic inflammation, a mouse model that shares features with the human disease. We found that IL-17 cytokines/CIKS-mediated signaling into keratinocytes is essential for neutrophilic microabscess formation and contributes to hyperproliferation and markedly attenuated differentiation of keratinocytes, at least in part via direct effects. In contrast, IL-17 cytokines/CIKS-mediated signaling into nonkeratinocytes, particularly into dermal fibroblasts, promotes cellular infiltration and, importantly, leads to enhanced the accumulation of IL-17–producing γδT cells in skin, comprising a positive feed-forward mechanism. Thus, CIKS-mediated signaling is central in the development of both dermal and epidermal hallmarks of psoriasis, inducing distinct pathologies via target cell-specific effects. CIKS-mediated signaling represents a potential therapeutic target in psoriasis.

Anti-inflammatory functions of the “apoptotic” caspases

The two main known functions of the caspases act antagonistically in regulating inflammation. “Inflammatory” caspases trigger inflammation by catalyzing the processing of IL‐1β precursors and other proinflammatory cytokines. In contrast, “apoptotic” caspases safeguard against the triggering of inflammation by imposing a cell‐death form that withholds release of alarmins by dying cells and dictates generation of anti‐inflammatory mediators. These antagonizing functions are exerted by evolution‐related mechanisms. Studies of the function of caspase‐8, an enzyme‐mediating apoptotic cell‐death induction in response to TNF‐family ligands, reveal that it blocks inflammation in additional ways. One way is by restricting activation of the RIG‐I complex by foreign ribonucleic acid. Chronic skin inflammation in mice with caspase‐8–deficient epidermis is associated with constitutive activation of the RIG‐I complex in keratinocytes. This activation is apparently prompted by nucleic acids released from epidermal cells that disintegrate during cornification, and becomes chronic because it is not restricted by caspase‐8.

Anti-inflammatory Functions of Caspase-8

Explorations of the functions of receptors of the TNF/NGF family have led to the discovery of various signaling proteins, many of which were later found to mediate effects of other inducers as well. We now have quite detailed knowledge of the mechanisms and molecular complexes by which some of the signaling proteins mediate these additional effects. This, however, is not the case for caspase-8. This signaling protein, which was initially identified as the proximal enzyme in the induction of apoptotic death by the death receptors, was subsequently reported to serve additional functions independently of those receptors. Whereas the mechanisms by which caspase-8 mediates cell death induction have been described in detail, almost nothing is known of the way it serves other functions. Findings that we presented at the 12th Biennial TNF Conference indicate that one of the physiological roles of this enzyme is to suppress inflammation. We further showed that one way by which caspase-8 does this is by associating with the RIG-I signaling complex and inhibiting some of the signaling mechanisms that are triggered upon formation of this complex in response to cytoplasmic ribonucleic acid. We illustrated the physiological role of caspase-8 in suppressing excessive inflammation by describing a fatal chronic skin inflammatory disease that occurs in mice as a result of deletion of caspase-8 from the epidermis.

Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease

1. 1. Kovalenko, 2. et al . 2009. J. Exp. Med. doi: 10.1084/jem.20090616 [OpenUrl][1][Abstract/FREE Full Text][2] [1]: {openurl}?query=rft_id%253Dinfo%253Adoi%252F10.1084%252Fjem.20090616%26rft_id%253Dinfo%253Apmid%252F19720838%26rft.genre%253Darticle%26rft_val_fmt%