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Multivariate modeling identifies neutrophil- and Th17-related factors as differential serum biomarkers of chronic murine colitis.

McBee ME, Zeng Y, Parry N, Nagler CR, Tannenbaum SR, Schauer DB - PLoS ONE (2010)

Bottom Line: In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon.Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis.Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.

View Article: PubMed Central - PubMed

Affiliation: Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. mmcbee@bsd.uchicago.edu

ABSTRACT

Background: Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling.

Methodology/principal findings: Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4(-/-) x IL-10(-/-) mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis.

Conclusions/significance: Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.

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Colonic and serum cytokines associated with acute C. rodentium-induced colitis.Cytokines in colon tissue (A) and serum (B) of uninfected (Cr−; n = 10 tissue, n = 9 serum) and C. rodentium infected (Cr+; n = 10) mice at 14 DPI. Colon values were normalized to total protein. Line indicates mean value. * P<0.05, ** P<0.01, *** P<0.001 by unpaired Student's t-test.
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pone-0013277-g002: Colonic and serum cytokines associated with acute C. rodentium-induced colitis.Cytokines in colon tissue (A) and serum (B) of uninfected (Cr−; n = 10 tissue, n = 9 serum) and C. rodentium infected (Cr+; n = 10) mice at 14 DPI. Colon values were normalized to total protein. Line indicates mean value. * P<0.05, ** P<0.01, *** P<0.001 by unpaired Student's t-test.

Mentions: The complex colonic cytokine milieu present during peak severity of acute C. rodentium colitis has not previously been analyzed in detail at the protein level. To gain additional biological insight into the active disease process 23 cytokines from frozen full-thickness colon sections at 14 DPI were analyzed. Chemokines KC and MCP-1 and the cytokines IL-1β, IL-6, IL-12/23p40, and IL-17 were elevated in colon tissue of Cr+ mice, Figure 2A, confirming previous studies performed at the mRNA level [8], [13], [14], [20]. Newly identified factors induced by C. rodentium infection are cytokines associated with T cell and neutrophil proliferation (IL-2 and G-CSF) and chemokines (RANTES, MIP-1α, and MIP-1β), Figure 2A and Figure S2A. Of the 23 cytokines measured only five were significantly elevated in the serum at 14 DPI, Figure 2B and Figure S2B. Of note was the elevation of IFN-γ in serum indicating, perhaps, a broader systemic role for this cytokine in disease resolution. Chemotactic and proliferation promoting cytokines G-CSF, IL-2, and RANTES were elevated in serum in addition to tissue, Figure 2B, indicating that the presence of acute intestinal inflammation is detectable both locally and systemically.


Multivariate modeling identifies neutrophil- and Th17-related factors as differential serum biomarkers of chronic murine colitis.

McBee ME, Zeng Y, Parry N, Nagler CR, Tannenbaum SR, Schauer DB - PLoS ONE (2010)

Colonic and serum cytokines associated with acute C. rodentium-induced colitis.Cytokines in colon tissue (A) and serum (B) of uninfected (Cr−; n = 10 tissue, n = 9 serum) and C. rodentium infected (Cr+; n = 10) mice at 14 DPI. Colon values were normalized to total protein. Line indicates mean value. * P<0.05, ** P<0.01, *** P<0.001 by unpaired Student's t-test.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2957404&req=5

pone-0013277-g002: Colonic and serum cytokines associated with acute C. rodentium-induced colitis.Cytokines in colon tissue (A) and serum (B) of uninfected (Cr−; n = 10 tissue, n = 9 serum) and C. rodentium infected (Cr+; n = 10) mice at 14 DPI. Colon values were normalized to total protein. Line indicates mean value. * P<0.05, ** P<0.01, *** P<0.001 by unpaired Student's t-test.
Mentions: The complex colonic cytokine milieu present during peak severity of acute C. rodentium colitis has not previously been analyzed in detail at the protein level. To gain additional biological insight into the active disease process 23 cytokines from frozen full-thickness colon sections at 14 DPI were analyzed. Chemokines KC and MCP-1 and the cytokines IL-1β, IL-6, IL-12/23p40, and IL-17 were elevated in colon tissue of Cr+ mice, Figure 2A, confirming previous studies performed at the mRNA level [8], [13], [14], [20]. Newly identified factors induced by C. rodentium infection are cytokines associated with T cell and neutrophil proliferation (IL-2 and G-CSF) and chemokines (RANTES, MIP-1α, and MIP-1β), Figure 2A and Figure S2A. Of the 23 cytokines measured only five were significantly elevated in the serum at 14 DPI, Figure 2B and Figure S2B. Of note was the elevation of IFN-γ in serum indicating, perhaps, a broader systemic role for this cytokine in disease resolution. Chemotactic and proliferation promoting cytokines G-CSF, IL-2, and RANTES were elevated in serum in addition to tissue, Figure 2B, indicating that the presence of acute intestinal inflammation is detectable both locally and systemically.

Bottom Line: In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon.Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis.Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.

View Article: PubMed Central - PubMed

Affiliation: Biological Engineering Department, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America. mmcbee@bsd.uchicago.edu

ABSTRACT

Background: Diagnosis of chronic intestinal inflammation, which characterizes inflammatory bowel disease (IBD), along with prediction of disease state is hindered by the availability of predictive serum biomarker. Serum biomarkers predictive of disease state will improve trials for therapeutic intervention, and disease monitoring, particularly in genetically susceptible individuals. Chronic inflammation during IBD is considered distinct from infectious intestinal inflammation thereby requiring biomarkers to provide differential diagnosis. To address whether differential serum biomarkers could be identified in murine models of colitis, immunological profiles from both chronic spontaneous and acute infectious colitis were compared and predictive serum biomarkers identified via multivariate modeling.

Methodology/principal findings: Discriminatory multivariate modeling of 23 cytokines plus chlorotyrosine and nitrotyrosine (protein adducts from reactive nitrogen species and hypochlorite) in serum and tissue from two murine models of colitis was performed to identify disease-associated biomarkers. Acute C. rodentium-induced colitis in C57BL/6J mice and chronic spontaneous Helicobacter-dependent colitis in TLR4(-/-) x IL-10(-/-) mice were utilized for evaluation. Colon profiles of both colitis models were nearly identical with chemokines, neutrophil- and Th17-related factors highly associated with intestinal disease. In acute colitis, discriminatory disease-associated serum factors were not those identified in the colon. In contrast, the discriminatory predictive serum factors for chronic colitis were neutrophil- and Th17-related factors (KC, IL-12/23p40, IL-17, G-CSF, and chlorotyrosine) that were also elevated in colon tissue. Chronic colitis serum biomarkers were specific to chronic colitis as they were not discriminatory for acute colitis.

Conclusions/significance: Immunological profiling revealed strikingly similar colon profiles, yet distinctly different serum profiles for acute and chronic colitis. Neutrophil- and Th17-related factors were identified as predictive serum biomarkers of chronic colitis, but not acute colitis, despite their presence in colitic tissue of both diseases thereby demonstrating the utility of mathematical modeling for identifying disease-associated serum biomarkers.

Show MeSH
Related in: MedlinePlus