Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A

Kawaguchi, Yasushi; Hara, Masako; Wright, Timothy M.

doi:10.1172/jci4304

Cited by 180 publications

(119 citation statements)

References 32 publications

Supporting

Mentioning

115

Contrasting

Unclassified

Order By: Relevance

“…We observed no specific bands below the 30-kDa molecule (data not shown). Thus, we con-cluded that intracellular IL-1␣ was almost pre-IL-1␣ (31 kDa) in SSc fibroblasts, consistent with our previous studies (3)(4)(5).…”

Section: Immunoprecipitation (Ip)supporting

confidence: 92%

“…Because skin thickening manifests in most patients, researchers have analyzed the molecular and biological functions of lesional skin fibroblasts that are derived from SSc patients (2). In previous reports we demonstrated that SSc fibroblasts expressed IL-1␣ mRNA constitutively and that aberrant production of precursor IL-1␣ (pre-IL-1␣) contributed to skin fibrosis in SSc (3)(4)(5). IL-1␣ is a multifunctional molecule that is involved in a variety of inflammatory disorders, including sepsis, arthritis, myositis, psoriasis, periodontitis, and Alzheimer's disease (6).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

Kawaguchi

Nishimagi²,

Tochimoto³

et al. 2006

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

Self Cite

View full text Add to dashboard Cite

The aberrant production of precursor IL-1␣ (pre-IL-1␣) in skin fibroblasts that are derived from systemic sclerosis (SSc) is associated with the induction of IL-6 and procollagen, which contributes to the fibrosis of SSc. However, little is understood about how intracellular pre-IL-1␣ regulates the expression of the other molecules in fibroblasts. We report here that pre-IL-1␣ can form a complex with IL-1␣-binding proteins that is translocated into the nuclei of fibroblasts. Immunoprecipitation that used anti-human IL-1␣ Ab and 35 S-labeled nuclear extracts of fibroblasts showed three specific bands (Ϸ31, 35, and 65 kDa). The 31-kDa molecule was identified as pre-IL-1␣, and the 35-and 65-kDa molecules might be pre-IL-1␣-binding proteins. A partial sequencing for the 10 aa from the N-terminals of the molecules showed 100% homology for HAX-1 (HS1-associated protein X-1) and IL-1 receptor type II (IL-1RII). Suppression of the genes of HAX-1 or IL-1RII induced the inhibitory effects of IL-1 signal transduction, including production of IL-6 and procollagen, by fibroblasts. In particular, pre-IL-1␣ was not translocated into the nucleus by an inhibition of HAX-1. These findings reveal that nuclear localization of pre-IL-1␣ depends on the binding to HAX-1 and that biological activities might be elicited by the binding to both HAX-1 and IL-1RII in SSc fibroblasts.IL-1 receptor type II ͉ HS1-associated protein X-1 ͉ fibrosis ͉ collagen ͉ IL-6

show abstract

Section: Immunoprecipitation (Ip)supporting

confidence: 92%

mentioning

confidence: 99%

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

Kawaguchi

Nishimagi²,

Tochimoto³

et al. 2006

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…As an intracellular molecule, IL-1␣ has been also shown to be inserted in the membrane and act in a juxtacrine manner (3,4,23). However, there is growing evidence for intracellular functions of IL-1␣, including promotion of senesence (12), cell growth and differentiation (7) and regulation of gene expression (24).…”

Section: Discussionmentioning

confidence: 99%

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

Werman

Werman-Venkert

White

et al. 2004

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

336

283

View full text Add to dashboard Cite

Although most cytokines are studied for biological effects after engagement of their specific cell surface membrane receptors, increasing evidence suggests that some function in the nucleus. In the present study, the precursor form of IL-1␣ was overexpressed in various cells and assessed for activity in the presence of saturating concentrations of IL-1 receptor antagonist to prevent receptor signaling. Initially diffusely present in the cytoplasm of resting cells, IL-1␣ translocated to the to nucleus after activation by endotoxin, a Toll-like receptor ligand. The IL-1␣ precursor, but not the C-terminal mature form, activated the transcriptional machinery in the GAL4 system by 90-fold; a 50-fold increase was observed using only the IL-1␣ propiece, suggesting that transcriptional activation was localized to the N terminus where the nuclear localization sequence resides. Under conditions of IL-1 receptor blockade, intracellular overexpression of the precursor and propiece forms of IL-1␣ were sufficient to activate NF-B and AP-1. Stable transfectants overproducing precursor IL-1␣ released the cytokines IL-8 and IL-6 but also exhibited a significantly lower threshold of activation to subpicomolar concentrations of tumor necrosis factor ␣ or IFN-␥. Thus, intracellular functions of IL-1␣ might play an unforeseen role in the genesis of inflammation. During disease-driven events, the cytosolic precursor moves to the nucleus, where it augments transcription of proinflammatory genes. Because this mechanism of action is not affected by extracellular inhibitors, reducing intracellular functions of IL-1␣ might prove beneficial in some inflammatory conditions.

show abstract

“…IL-1α is constitutively expressed in human keratinocytes, other cells synthesise and release IL-1α under stimulation 8,9 . IL-1β is produced by wide range of cells, particularly of monocytemacrophage lineage.…”

Section: Characteristics Of Il-1 Family Membersmentioning

confidence: 99%

“…SSc fibroblasts are characteristic by increased production of IL-1α, IL-6 and PDGF-A, the key mediators of collagen synthesis, which mediate an excessive extracellular matrix synthesis 9 . IL-1β plays a crucial role also in "destructive" organ-specific autoimmunity in Hashimoto's thyreoiditis by induction of efficient autoantigen presentation via costimulatory molecules and Fas/FasL-mediated apoptosis of thyroid follicular cells 58 .…”

Section: Autoimmune Diseasesmentioning

confidence: 99%

Interleukin-1 Family: From Genes to Human Disease

Laurincová¹

2000

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

View full text Add to dashboard Cite

Interleukin-1 (IL-1) is one of the most potent proinflammatory cytokines involved both in physiological immune responses and in the development of various immunopathological disorders. The members of IL-1 family form a complex system with tight regulatory mechanisms and clarifying their role in disease remains in the centre of research interests. This review article except of summarising recent findings about IL-1 family members focuses on associations of IL-1 gene complex polymorphisms with human diseases.

show abstract

Endogenous IL-1α from systemic sclerosis fibroblasts induces IL-6 and PDGF-A

Cited by 180 publications

References 32 publications

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

Intracellular IL-1α-binding proteins contribute to biological functions of endogenous IL-1α in systemic sclerosis fibroblasts

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

Interleukin-1 Family: From Genes to Human Disease

Contact Info

Product

Resources

About