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LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC.
Thomas, Gregory; Frederick, Elizabeth; Thompson, Lisa; Bar-Or, Raphael; Mulugeta, Yetti; Hausburg, Melissa; Roshon, Michael; Mains, Charles; Bar-Or, David.
  • Thomas G; Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA.
  • Frederick E; Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA.
  • Thompson L; Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA.
  • Bar-Or R; Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA.
  • Mulugeta Y; Trauma Research Department, Swedish Medical Center, 501 E. Hampden Ave. Rm 4-454, Englewood, CO, 80113, USA.
  • Hausburg M; Trauma Research Department, St. Anthony Hospital, 11600 W 2nd Pl, Lakewood, CO, 80228, USA.
  • Roshon M; Trauma Research Department, Penrose Hospital, 2222 N Nevada Ave, Colorado Springs, CO, 80907, USA.
  • Mains C; Centura Health Systems, 9100 E. Mineral Cir, Centennial, CO, 80112, USA.
  • Bar-Or D; Ampio Pharmaceuticals Inc, 373 Inverness Parkway Suite 200, Englewood, CO, 80122, USA.
J Transl Med ; 18(1): 452, 2020 11 30.
Article in English | MEDLINE | ID: covidwho-948411
Semantic information from SemMedBD (by NLM)
1. cytokine CAUSES Inflammatory disorder
Subject
cytokine
Predicate
CAUSES
Object
Inflammatory disorder
2. Evaluation procedure TREATS Degenerative polyarthritis
Subject
Evaluation procedure
Predicate
TREATS
Object
Degenerative polyarthritis
3. Evaluation procedure TREATS Inflammatory Response
Subject
Evaluation procedure
Predicate
TREATS
Object
Inflammatory Response
4. Biopharmaceuticals ASSOCIATED_WITH COVID-19
Subject
Biopharmaceuticals
Predicate
ASSOCIATED_WITH
Object
COVID-19
5. Transcriptio AFFECTS C0085732
Subject
Transcriptio
Predicate
AFFECTS
Object
C0085732
6. Lipopolysaccharides AUGMENTS Peripheral blood mononuclear cell (cell)
Subject
Lipopolysaccharides
Predicate
AUGMENTS
Object
Peripheral blood mononuclear cell (cell)
7. TRANSCRIPTION FACTOR INTERACTS_WITH cytokine
Subject
TRANSCRIPTION FACTOR
Predicate
INTERACTS_WITH
Object
cytokine
8. Assay USES Tracer
Subject
Assay
Predicate
USES
Object
Tracer
9. NF-kappa B INTERACTS_WITH cytokine
Subject
NF-kappa B
Predicate
INTERACTS_WITH
Object
cytokine
10. STAT Transcription Factors|SOAT1 INTERACTS_WITH cytokine
Subject
STAT Transcription Factors|SOAT1
Predicate
INTERACTS_WITH
Object
cytokine
11. DNA Binding PROCESS_OF transcription factor p91
Subject
DNA Binding
Predicate
PROCESS_OF
Object
transcription factor p91
12. DNA Binding PROCESS_OF NF-kappa B
Subject
DNA Binding
Predicate
PROCESS_OF
Object
NF-kappa B
13. NF-kappa B STIMULATES Luciferases
Subject
NF-kappa B
Predicate
STIMULATES
Object
Luciferases
14. Patient Discharge USES interleukin-
Subject
Patient Discharge
Predicate
USES
Object
interleukin-
15. research study USES antagonists
Subject
research study
Predicate
USES
Object
antagonists
16. SOAT1 gene|SOAT1 INHIBITS TRANSCRIPTION FACTOR
Subject
SOAT1 gene|SOAT1
Predicate
INHIBITS
Object
TRANSCRIPTION FACTOR
17. SOAT1 gene|SOAT1 INHIBITS Aryl Hydrocarbon Receptor
Subject
SOAT1 gene|SOAT1
Predicate
INHIBITS
Object
Aryl Hydrocarbon Receptor
18. SOAT1 gene|SOAT1 INHIBITS PPAR gamma
Subject
SOAT1 gene|SOAT1
Predicate
INHIBITS
Object
PPAR gamma
19. cytokine CAUSES Inflammatory disorder
Subject
cytokine
Predicate
CAUSES
Object
Inflammatory disorder
20. Evaluation procedure TREATS Degenerative polyarthritis
Subject
Evaluation procedure
Predicate
TREATS
Object
Degenerative polyarthritis
21. Evaluation procedure TREATS Inflammatory Response
Subject
Evaluation procedure
Predicate
TREATS
Object
Inflammatory Response
22. Biopharmaceuticals ASSOCIATED_WITH COVID-19
Subject
Biopharmaceuticals
Predicate
ASSOCIATED_WITH
Object
COVID-19
23. Transcription, Genetic AFFECTS Ability
Subject
Transcription, Genetic
Predicate
AFFECTS
Object
Ability
24. Lipopolysaccharides AUGMENTS Peripheral blood mononuclear cell (cell)
Subject
Lipopolysaccharides
Predicate
AUGMENTS
Object
Peripheral blood mononuclear cell (cell)
25. TRANSCRIPTION FACTOR INTERACTS_WITH cytokine
Subject
TRANSCRIPTION FACTOR
Predicate
INTERACTS_WITH
Object
cytokine
26. Assay USES Tracer
Subject
Assay
Predicate
USES
Object
Tracer
27. NF-kappa B INTERACTS_WITH cytokine
Subject
NF-kappa B
Predicate
INTERACTS_WITH
Object
cytokine
28. STAT Transcription Factors|SOAT1 INTERACTS_WITH cytokine
Subject
STAT Transcription Factors|SOAT1
Predicate
INTERACTS_WITH
Object
cytokine
29. DNA Binding PROCESS_OF transcription factor p91
Subject
DNA Binding
Predicate
PROCESS_OF
Object
transcription factor p91
30. DNA Binding PROCESS_OF NF-kappa B
Subject
DNA Binding
Predicate
PROCESS_OF
Object
NF-kappa B
31. NF-kappa B STIMULATES Luciferases
Subject
NF-kappa B
Predicate
STIMULATES
Object
Luciferases
32. Patient Discharge USES interleukin-1, beta
Subject
Patient Discharge
Predicate
USES
Object
interleukin-1, beta
33. research study USES antagonists
Subject
research study
Predicate
USES
Object
antagonists
34. SOAT1 gene|SOAT1 INHIBITS TRANSCRIPTION FACTOR
Subject
SOAT1 gene|SOAT1
Predicate
INHIBITS
Object
TRANSCRIPTION FACTOR
35. SOAT1 gene|SOAT1 INHIBITS Aryl Hydrocarbon Receptor
Subject
SOAT1 gene|SOAT1
Predicate
INHIBITS
Object
Aryl Hydrocarbon Receptor
36. SOAT1 gene|SOAT1 INHIBITS PPAR gamma
Subject
SOAT1 gene|SOAT1
Predicate
INHIBITS
Object
PPAR gamma
ABSTRACT

BACKGROUND:

Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional programs can cause an overabundance of pro-inflammatory, classically activated macrophage type 1 (M1) and/or helper T cell type 1 (Th1) products, such as IFNγ, TNFα, IL1-ß, and IL12, that prevent immune switching to resolution and healing. The low molecular weight fraction of human serum albumin (LMWF5A) is a novel biologic drug that is currently under clinical investigation for the treatment of osteoarthritis and the hyper-inflammatory response associated with COVID-19. This study aims to elucidate transcriptional mechanisms of action involved with the ability of LMWF5A to reduce pro-inflammatory cytokine release.

METHODS:

ELISA arrays were used to identify cytokines and chemokines influenced by LMWF5A treatment of LPS-stimulated peripheral blood mononuclear cells (PBMC). The resulting profiles were analyzed by gene enrichment to gain mechanistic insight into the biologic processes and transcription factors (TFs) underlying the identified differentially expressed cytokines. DNA-binding ELISAs, luciferase reporter assays, and TNFα or IL-1ß relative potency were then employed to confirm the involvement of enriched pathways and TFs.

RESULTS:

LMWF5A was found to significantly inhibit a distinct set of pro-inflammatory cytokines (TNFα, IL-1ß, IL-12, CXCL9, CXCL10, and CXCL11) associated with pro-inflammatory M1/Th1 immune profiles. Gene enrichment analysis also suggests these cytokines are, in part, regulated by NF-κB and STAT transcription factors. Data from DNA-binding and reporter assays support this with LMWF5A inhibition of STAT1α DNA-binding activity as well as a reduction in overall NF-κB-driven luciferase expression. Experiments using antagonists specific for the immunomodulatory and NF-κB/STAT-repressing transcription factors, peroxisome proliferator-activated receptor (PPAR)γ and aryl hydrocarbon receptor (AhR), indicate these pathways are involved in the LMWF5A mechanisms of action by reducing LMWF5A drug potency as measured by TNFα and IL-1ß release.

CONCLUSION:

In this report, we provide evidence that LMWF5A reduces pro-inflammatory cytokine release by activating the immunoregulatory transcription factors PPARγ and AhR. In addition, our data indicate that LMWF5A suppresses NF-κB and STAT1α pro-inflammatory pathways. This suggests that LMWF5A acts through these mechanisms to decrease pro-inflammatory transcription factor activity and subsequent inflammatory cytokine production.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Leukocytes, Mononuclear / Cytokines / Serum Albumin, Human / Inflammation Type of study: Prognostic study Limits: Humans Language: English Journal: J Transl Med Year: 2020 Document Type: Article Affiliation country: S12967-020-02626-z

Full text: Available Collection: International databases Database: MEDLINE Main subject: Leukocytes, Mononuclear / Cytokines / Serum Albumin, Human / Inflammation Type of study: Prognostic study Limits: Humans Language: English Journal: J Transl Med Year: 2020 Document Type: Article Affiliation country: S12967-020-02626-z