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Attenuation of interleukin 8-induced nasal inflammation by an inhibitor peptide
J A Cooper1, A L Ridgeway, J Pearson
1Pulmonary Sections, Birmingham Veterans Affairs Medical Center, and University of Alabama at Birmingham, Birmingham, Alabama, USA.
Abstract:
Polymorphonuclear neutrophils (PMNs) infiltrate tissue in response to chemoattractants, including interleukin 8 (IL-8). Infiltrating PMNs clear microorganisms but also cause tissue damage. We previously reported the presence in human bronchial lavage of a peptide that inhibits PMN functions. The current project assessed (1) effects of a synthetic analog of this peptide (synthetic neutrophil inhibitor peptide, SNIP) on IL-8-induced nasal inflammation in humans, (2) effects of SNIP on PMN apoptosis and chemotaxis, (3) specific binding of SNIP to PMNs, and (4) evidence of larger molecules with the SNIP sequence. Results show that SNIP attenuates IL-8-induced nasal inflammation, inhibits in vitro PMN chemotaxis to IL-8, and accentuates PMNs apoptosis. PMNs contain specific SNIP-binding sites and the integrin CR3 (CD11b/CD18), or a CR3-associated molecule, is one SNIP-binding molecule. Chemotaxis to IL-8 is most potently inhibited by SNIP in the presence of fibrinogen, a CR3 ligand. Antiserum against the SNIP sequence recognizes a 70-kDa protein in bronchoalveolar lavage and an anti-SNIP immunoaffinity column binds a 70-kDa protein in U937 cell culture supernatant. U937 cell mRNA contains a 1.8-kb transcript detected with degenerate oligonucleotides designed from the SNIP sequence. These studies demonstrate that a synthetic inhibitor peptide can attenuate in vivo nasal inflammation through downregulatory effects on PMNs.
Insights
A synthetic neutrophil inhibitor peptide (SNIP) reduces nasal inflammation by decreasing the movement and increasing the cell death of neutrophils. SNIP also binds to specific sites on neutrophils, suggesting a targeted anti-inflammatory mechanism.
Area of Science:
- Immunology
- Inflammation Research
- Molecular Biology
Background:
- Polymorphonuclear neutrophils (PMNs) are key in host defense but can cause tissue damage during inflammation.
- Interleukin 8 (IL-8) is a chemoattractant that drives PMN infiltration.
- A previously identified peptide inhibits PMN functions.
Purpose of the Study:
- To evaluate the effects of a synthetic neutrophil inhibitor peptide (SNIP) on IL-8-induced nasal inflammation in humans.
- To investigate SNIP's impact on PMN apoptosis and chemotaxis.
- To identify SNIP-binding sites on PMNs and related molecules.
Main Methods:
- Human clinical trials assessing IL-8-induced nasal inflammation with SNIP.
- In vitro assays for PMN apoptosis and chemotaxis.
- Biochemical assays to identify SNIP-binding molecules on PMNs, including CR3 (CD11b/CD18).
- Analysis of bronchoalveolar lavage and cell culture supernatant for SNIP-related proteins and mRNA.
Main Results:
- SNIP significantly attenuated IL-8-induced nasal inflammation.
- SNIP inhibited PMN chemotaxis towards IL-8 in vitro and enhanced PMN apoptosis.
- Specific SNIP-binding sites were identified on PMNs, with integrin CR3 or associated molecules implicated.
- A 70-kDa protein containing the SNIP sequence was detected in biological samples.
Conclusions:
- SNIP effectively reduces in vivo nasal inflammation.
- SNIP exerts its anti-inflammatory effects by downregulating PMN functions, including chemotaxis and survival.
- The findings suggest SNIP or related molecules are potential therapeutic agents for inflammatory conditions.