Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity

Wang, Binghe; Feliciani, Claudio; Howell, Brandon G.; Freed, Irwin; Cai, Qinchao; Watanabe, Hideaki; Sauder, Daniel N.

doi:10.4049/jimmunol.168.7.3303

Cited by 55 publications

(43 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…IL-18 has been shown to play an essential role in migration of LCs into draining lymph nodes by an IL-1␤-and TNF-␣-dependent mechanism . IL-18 has also been implicated in IL-12-driven IFN-␥ production by T H 1 cells, thus contributing to DTH responses in the skin (Wang et al, 2002). As shown in Fig.…”

Section: Discussionmentioning

confidence: 97%

(S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an Orally Available Selective Interleukin (IL)-Converting Enzyme/Caspase-1 Inhibitor, Exhibits Potent Anti-Inflammatory Activities by Inhibiting the Release of IL-1β and IL-18

Wannamaker

Davies²,

Namchuk³

et al. 2007

J Pharmacol Exp Ther

268

174

View full text Add to dashboard Cite

(S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765) is an orally absorbed prodrug of (S)-3-({1-[(S)-1-((S)-2-{[1-(4-amino-3-chlorophenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidin-2-yl]-methanoyl}-amino)-4-oxo-butyric acid (VRT-043198), a potent and selective inhibitor of interleukin-converting enzyme/ caspase-1 subfamily caspases. VRT-043198 exhibits 100-to 10,000-fold selectivity against other caspase-3 and -6 to -9. The therapeutic potential of VX-765 was assessed by determining the effects of VRT-043198 on cytokine release by monocytes in vitro and of orally administered VX-765 in several animal models in vivo. In cultures of peripheral blood mononuclear cells and whole blood from healthy subjects stimulated with bacterial products, VRT-043198 inhibited the release of interleukin (IL)-1␤ and IL-18, but it had little effect on the release of several other cytokines, including IL-1␣, tumor necrosis factor-␣, IL-6 and IL-8. In contrast, VRT-043198 had little or no demonstrable activity in cellular models of apoptosis, and it did not affect the proliferation of activated primary T cells or T-cell lines. VX-765 was efficiently converted to VRT-043198 when administered orally to mice, and it inhibited lipopolysaccharide-induced cytokine secretion. In addition, VX-765 reduced disease severity and the expression of inflammatory mediators in models of rheumatoid arthritis and skin inflammation. These data suggest that VX-765 is a novel cytokine inhibitor useful for treatment of inflammatory diseases.The interleukin-converting enzyme (ICE), also known as caspase-1, is the cysteine protease that cleaves pro-interleukin (IL)-1␤ and pro-IL-18 to form the mature, active cytokines IL-1␤ and IL-18, respectively. IL-1␤ and IL-18 have important roles in the acute and chronic stages of inflammatory immune responses (for review, see Braddock and Quinn, 2004). IL-1␤ induces the expression of several mediators of immune cell response, including tumor necrosis factor (TNF)-␣, IL-6, cyclooxygenase-2, chemokines, Article, publication date, and citation information can be found at

show abstract

Section: Discussionmentioning

confidence: 97%

(S)-1-((S)-2-{[1-(4-Amino-3-chloro-phenyl)-methanoyl]-amino}-3,3-dimethyl-butanoyl)-pyrrolidine-2-carboxylic acid ((2R,3S)-2-ethoxy-5-oxo-tetrahydro-furan-3-yl)-amide (VX-765), an Orally Available Selective Interleukin (IL)-Converting Enzyme/Caspase-1 Inhibitor, Exhibits Potent Anti-Inflammatory Activities by Inhibiting the Release of IL-1β and IL-18

Wannamaker

Davies²,

Namchuk³

et al. 2007

J Pharmacol Exp Ther

268

174

View full text Add to dashboard Cite

show abstract

“…Although the p40 molecule detected by ELISA may be an antagonist homodimer (p40) 2 (12), others have reported that p40 in the skin functions like the heterodimer (18). Another Th1-inducing cytokine, IL-18, is also detected in the dermal supernatants and is known to be produced by keratinocytes (37) and Langerhans cells (42). It can act in concert with IL-12 and other cytokines, such as IL-1␤, tumor necrosis factor alpha, and IL-6, in the proinflammatory immune response (29).…”

Section: Discussionmentioning

confidence: 99%

Interleukin-12 p40 Secretion by Cutaneous CD11c⁺and F4/80⁺Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity toSchistosomamansoni

et al. 2003

View full text Add to dashboard Cite

Radiation-attenuated (RA) schistosome larvae are potent stimulators of innate immune responses at the skin site of exposure (pinna) that are likely to be important factors in the development of Th1-mediated protective immunity. In addition to causing an influx of neutrophils, macrophages, and dendritic cells (DCs) into the dermis, RA larvae induced a cascade of chemokine and cytokine secretion following in vitro culture of pinna biopsy samples. While macrophage inflammatory protein 1␣ and interleukin-1␤ (IL-1␤) were produced transiently within the first few days, the Th1-promoting cytokines IL-12 and IL-18 were secreted at high levels until at least day 14. Assay of C3H/HeJ mice confirmed that IL-12 secretion was not due to lipopolysaccharide contaminants binding Toll-like receptor 4. Significantly, IL-12 p40 secretion was sustained in pinnae from vaccinated mice but not in those from nonprotected infected mice. In contrast, IL-10 was produced from both vaccinated and infected mice. This cytokine regulates IL-12-associated dermal inflammation, since in vaccinated IL-10 ؊/؊ mice, pinna thickness was greatly increased concurrent with elevated levels of IL-12 p40. A significant number of IL-12 p40 ؉ cells were detected as emigrants from in vitro-cultured pinnae, and most were within a population of rare large granular cells that were Ia ؉ , consistent with their being antigen-presenting cells. Labeling of IL-12 ؉ cells for CD11c, CD205, CD8␣, CD11b, and F4/80 indicated that the majority were myeloid DCs, although a proportion were CD11c ؊ F4/80 ؉ , suggesting that macrophages were an additional source of IL-12 in the skin.The processes leading to the induction of polarized T-helper lymphocyte populations following exposure of the host to infectious pathogens are believed to involve interactions between the innate and acquired immune systems at the initial site of infection (24). In this context, the skin is a major barrier across which many infectious agents, including the parasitic helminth Schistosoma mansoni, gain entry to the host. This site is populated by an array of immune-competent accessory cells acting as sentinels, which are an important source of cytokines and chemokines responsible for amplifying the inflammatory response by activating resident cells and recruiting additional cells (9, 49). Cytokines also have an important influence on Th cell development, with interleukin-12 (IL-12), IL-18, tumor necrosis factor alpha, and IL-1␤ being key factors in the differentiation of Th1 cells (20,29).In our study, we examined innate immune responses elicited in the skin of mice exposed to radiation-attenuated (RA) larvae of S. mansoni. In this vaccine model, RA larvae induce Th1-type acquired immunity, which is characterized by the persistence of gamma interferon (IFN-␥)-secreting Th cells in the skin-draining lymph nodes (sdLN) (26) and confers 60 to 70% protection against a challenge infection (11). There is clear evidence that IL-12 is a critical component of this Th1-mediated protection (2, 47). In contrast,...

show abstract

“…Keratinocytes are able to produce IL-18, which can be processed and released under certain circumstances (143). In addition, Langerhans and dendritic cells in the skin are able to produce mature IL-18 in response to inflammatory stimulation (144,145). The role of IL-18 has not been examined in models of psoriasis.…”

Section: Psoriasismentioning

confidence: 99%

IL‐1, IL‐18, and IL‐33 families of cytokines

Arend

Palmer

Gabay

2008

Immunological Reviews

772

639

View full text Add to dashboard Cite

Summary: The interleukin-1 (IL-1), IL-18, and IL-33 families of cytokines are related by mechanism of origin, receptor structure, and signal transduction pathways utilized. All three cytokines are synthesized as precursor molecules and cleaved by the enzyme caspase-1 before or during release from the cell. The NALP-3 inflammasome is of crucial importance in generating active caspase-1. The IL-1 family contains two agonists, IL-1a and IL-1b, a specific inhibitor, IL-1 receptor antagonist (IL1Ra), and two receptors, the biologically active type IL-1R and inactive type II IL-1R. Both IL-1RI and IL-33R utilize the same interacting accessory protein (IL-1RAcP). The balance between IL-1 and IL-1Ra is important in preventing disease in various organs, and excess production of IL-1 has been implicated in many human diseases. The IL-18 family also contains a specific inhibitor, the IL-18-binding protein (IL-18BP), which binds IL-18 in the fluid phase. The IL-18 receptor is similar to the IL-1 receptor complex, including a single ligand-binding chain and a different interacting accessory protein. IL-18 provides an important link between the innate and adaptive immune responses. Newly described IL-33 binds to the orphan IL-1 family receptor T1/ST2 and stimulates T-helper 2 responses as well as mast cells.

show abstract

Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity

Cited by 55 publications

References 63 publications

Interleukin-12 p40 Secretion by Cutaneous CD11c⁺and F4/80⁺Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity toSchistosomamansoni

IL‐1, IL‐18, and IL‐33 families of cytokines

Contact Info

Product

Resources

About

Contribution of Langerhans Cell-Derived IL-18 to Contact Hypersensitivity

Cited by 55 publications

References 63 publications

Interleukin-12 p40 Secretion by Cutaneous CD11c+and F4/80+Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity toSchistosomamansoni

IL‐1, IL‐18, and IL‐33 families of cytokines

Contact Info

Product

Resources

About

Interleukin-12 p40 Secretion by Cutaneous CD11c⁺and F4/80⁺Cells Is a Major Feature of the Innate Immune Response in Mice That Develop Th1-Mediated Protective Immunity toSchistosomamansoni