The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Werman, Ariel; Werman-Venkert, Rachel; White, Rosalyn M.; Lee, Jae-Kwon; Werman, Batsheva; Krelin, Yakov; Voronov, Elena; Dinarello, Charles A.; Apte, Ron N.

doi:10.1073/pnas.0308705101

Cited by 335 publications

(298 citation statements)

References 38 publications

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“…The functions of these precursor domains are still being investigated. The most well characterized to date is the N terminus of pro-IL-1␣ (processed by calpain to the mature form (58)), which contains a nuclear localization sequence and can act as a transcription factor with or without the C-terminal region (59,60). IL-1␤ and IL-18 are processed by caspase-1.…”

Section: Discussionmentioning

confidence: 99%

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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Interleukin-1␤ (IL-1␤) is a master cytokine involved in initiating the innate immune response in vertebrates (Dinarello, C. A. (1994) FASEB J. 8, 1314 -1325). It is first synthesized as an inactive 269-residue precursor (pro-interleukin-1␤ or pro-IL-1␤). Pro-IL-1␤ requires processing by caspase-1 to generate the active, mature 153-residue cytokine. In this study, we combined hydrogen/deuterium exchange mass spectrometry, circular dichroism spectroscopy, and enzymatic digestion comparative studies to investigate the configurational landscape of pro-IL-1␤ and the role the N terminus plays in modulating the landscape. We find that the N terminus keeps pro-IL-1␤ in a protease-labile state while maintaining a core region of stability in the C-terminal region, the eventual mature protein. In mature IL-1␤, this highly protected region maps back to the area protected earliest in the NMR studies characterizing an on-route kinetic refolding intermediate. This protected region also encompasses two important functional loops that participate in the IL-1␤/receptor binding interface required for biological activity. We propose that the purpose of the N-terminal precursor region in pro-IL-1␤ is to suppress the function of the eventual mature region while keeping a structurally and also functionally important core region primed for the final folding into the native, active state of the mature protein. The presence of the self-inhibiting precursor region provides yet another layer of regulation in the life cycle of this important cytokine.Nearly all cell types respond to interleukin (IL)-1␤, 4 in a very sensitive manner, via binding to the interleukin-1 receptor type 1 (IL-1RI) (2). Although essential in the immune response, overproduction of IL-1␤ can lead to both acute (sepsis) as well as chronic (rheumatoid arthritis, atherosclerosis, obesity, and diabetes) disease states (3). Thus, the expression, activation, and secretion of this cytokine are tightly controlled (4). Although many cell types express IL-1␤, it is predominately produced and secreted by monocytes and macrophages (1). The protein is synthesized as a biologically inactive 269-residue precursor molecule, pro-interleukin-1␤ (pro-IL-1␤), and the 153-residue active mature IL-1␤ is generated from the C-terminal domain. Processing of the proprotein involves the recently discovered NALP-1 and NALP-3 inflammasomes, which are responsible for activating procaspase-1 (5). The inflammasome function is integral in wound repair as well as for combating infection (6 -9).In vivo, the 31-kDa pro-IL-1␤ precursor is processed to the active C-terminal 17-kDa form by the interleukin-1 converting enzyme, caspase-1 (10, 11). Caspase-1 is a cysteine protease that recognizes two cleavage sites in pro-IL-1␤, the Asp 27 2Gly 28 and Asp 116 2Ala 117 peptide bonds (Fig. 1A). These cleavage sites are conserved across mammals (12-14). The activation pathway is believed to proceed with cleavage first at Asp 27 2Gly 28 (site 1) followed by Asp 116 2Ala 117 (site 2). These processing events lead ...

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Section: Discussionmentioning

confidence: 99%

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Hailey¹,

Andersen³

et al. 2009

Journal of Biological Chemistry

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“…In contrast, the IL-1 precursor is not cleaved by caspase 1, IL-1␣ is not secreted from cells, and only in severe disease can one detect serum IL-1␣, which may result from its release from dying cells. IL-1␣ remains intracellular, where it can function as a DNA binding transcription factor, and perhaps as an oncogene (34)(35)(36). As shown in Figure 3, the IL-1␣ precursor is biologically active when inserted into the cell's membrane, oriented in such a manner that it binds to the type I IL-1 receptor and initiates signal transduction (37).…”

Section: Why 2 Il-1s?mentioning

confidence: 99%

The many worlds of reducing interleukin‐1

Dinarello¹

2005

Arthritis & Rheumatism

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“…The Nterminal domain of IL-1a contains a nuclear localization sequence, which mediates active nuclear import [10,11]. IL-1a has been reported to act within the nucleus to regulate cytokine transcription and RNA splicing [12,13]. In this study we sought to test the hypothesis that IL-1a nuclear import also inhibits IL-1a release following necrotic cell death.…”

Section: Introductionmentioning

confidence: 99%

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

2009

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Sterile inflammation is a host response to tissue injury that is mediated by damage-associated molecular patterns released from dead cells. Sterile inflammation worsens damage in a number of injury paradigms. The pro-inflammatory cytokine IL-1a is reported to be a damage-associated molecular pattern released from dead cells, and it is known to exacerbate brain injury caused by stroke. In the brain, IL-1a is produced by microglia, the resident brain macrophages. We found that IL-1a is actively trafficked to the nuclei of microglia, and hence tested the hypothesis that trafficking of IL-1a to the nucleus would inhibit its release following necrotic cell death, limiting sterile inflammation. Microglia subjected to oxygenglucose deprivation died via necrosis. Under these conditions, microglia expressing nuclear IL-1a released significantly less IL-1a than microglia with predominantly cytosolic IL-1a. The remaining IL-1a was immobilized in the nuclei of the dead cells. Thus, nuclear retention of IL-1a may serve to limit inflammation following cell death.Key words: IL-1a . Microglia . Necrosis . Nuclear retention . Sterile inflammation Supporting Information available online IntroductionSterile inflammation is a host response to tissue injury that can exacerbate the initial insult [1]. Intracellular molecules released from necrotic cells act as damage-associated molecular patterns (DAMP), signaling to the innate immune system that tissue injury has occurred [2]. IL-1a, a pro-inflammatory member of the IL-1 cytokine family [3], has recently been identified as a DAMP released from necrotic cells [4]. In addition, necrotic cell DAMP are reported to stimulate IL-1a production by immune cells, which further exacerbates sterile inflammation [1]. Experimental stroke in rodents elicits an inflammatory response that markedly exacerbates brain injury [5]. IL-1a is a key contributor to this injury, and its genetic ablation (along with IL-1b, a related cytokine) causes a 70% reduction in the brain injury caused by stroke [6].In the brain after injury (e.g. stroke, hemorrhage, trauma), IL-1 family cytokines are produced by microglia, the resident brain macrophages [7]. IL-1a is produced in the cytosol as a 31-kDa protein that, following release from necrotic cells, activates the type I IL-1 receptor on responsive cell membranes [8,9]. The Nterminal domain of IL-1a contains a nuclear localization sequence, which mediates active nuclear import [10,11]. IL-1a has been reported to act within the nucleus to regulate cytokine transcription and RNA splicing [12,13]. In this study we sought to test the hypothesis that IL-1a nuclear import also inhibits IL-1a release following necrotic cell death. We report that IL-1a nuclear import and intranuclear retention reduce IL-1a release from necrotic microglia. Thus, IL-1a nuclear retention by necrotic cells may inhibit injury-induced inflammation. Results IL-1a nuclear localization is inhibited at high cell densityTo investigate the effects of IL-1a nuclear localization on IL-1a release after ne...

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The precursor form of IL-1α is an intracrine proinflammatory activator of transcription

Cited by 335 publications

References 38 publications

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

Pro-interleukin (IL)-1β Shares a Core Region of Stability as Compared with Mature IL-1β While Maintaining a Distinctly Different Configurational Landscape

The many worlds of reducing interleukin‐1

Nuclear retention of IL‐1α by necrotic cells: A mechanism to dampen sterile inflammation

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