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Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment.

Janatpour MJ, Hudak S, Sathe M, Sedgwick JD, McEvoy LM - J. Exp. Med. (2001)

Bottom Line: Quantitative PCR analyses revealed the upregulation of many chemokines in the inflamed lymph node, including MCP-1 and MIG.HEVs did not express detectable levels of MCP-1; however, a subset of HEVs in inflamed lymph nodes in wild-type (but not tumor necrosis factor [TNF] mice) expressed MIG and this subset of HEVs preferentially supported monocyte binding.Together, these results suggest that the lymph node microenvironment can dictate the nature of molecules expressed on HEV subsets in a TNF-dependent fashion and that inflammation-induced MIG expression by HEVs can mediate monocyte recruitment.

View Article: PubMed Central - PubMed

Affiliation: DNAX Research Institute, Inc., Palo Alto, CA 94304, USA.

ABSTRACT
Monocytes recruited from the blood are key contributors to the nature of an immune response. While monocyte recruitment in a subset of immunopathologies has been well studied and largely attributed to the chemokine monocyte chemoattractant protein (MCP)-1, mechanisms mediating such recruitment to other sites of inflammation remain elusive. Here, we showed that localized inflammation resulted in an increased binding of monocytes to perifollicular high endothelial venules (HEVs) of lymph nodes draining a local inflammatory site. Quantitative PCR analyses revealed the upregulation of many chemokines in the inflamed lymph node, including MCP-1 and MIG. HEVs did not express detectable levels of MCP-1; however, a subset of HEVs in inflamed lymph nodes in wild-type (but not tumor necrosis factor [TNF] mice) expressed MIG and this subset of HEVs preferentially supported monocyte binding. Expression of CXCR3, the receptor for MIG, was detected on a small subset of peripheral blood monocytes and on a significant percentage of recruited monocytes. Most importantly, in both ex vivo and in vivo assays, neutralizing anti-MIG antibodies blocked monocyte binding to inflamed lymph node HEVs. Together, these results suggest that the lymph node microenvironment can dictate the nature of molecules expressed on HEV subsets in a TNF-dependent fashion and that inflammation-induced MIG expression by HEVs can mediate monocyte recruitment.

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MIG may play a direct role in monocyte-selective recruitment in inflammation. (A) Frozen lymph node sections were incubated with cells under nonstatic, cold conditions, and the ability of the HEVs to bind WEHI 78/24 was quantitated. Data is expressed as WEHI binding relative to an internal standard. Lymph nodes from inflamed (black bars) wild-type mice had a twofold increase in WEHI 78/24 binding to HEVs when compared to mice that were not inflamed (white bar; P value < 0.01). Furthermore, monocyte binding to inflamed HEVs from TNF  mice was similar to that observed in uninflamed wild-type mice, analogous to what was observed in vivo. This experiment was repeated three times. (B) The ex vivo assay described previously was performed on both inflamed lymph nodes (black bars) or lymph nodes that were not inflamed (white bars) in the presence of either a MIG neutralizing antibody (anti-MIG), a control (Control Ab), or no antibody at all (No Ab). In the presence of the control antibody, there was approximately a twofold increase in monocyte binding to inflamed HEVs compared to uninflamed HEVs (P value < 0.05). This was similar to that observed in the absence of antibody. In the presence of a MIG-neutralizing antibody, however, the degree of monocyte binding to inflamed HEVs was reduced to background levels. This experiment was repeated three times.
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fig5: MIG may play a direct role in monocyte-selective recruitment in inflammation. (A) Frozen lymph node sections were incubated with cells under nonstatic, cold conditions, and the ability of the HEVs to bind WEHI 78/24 was quantitated. Data is expressed as WEHI binding relative to an internal standard. Lymph nodes from inflamed (black bars) wild-type mice had a twofold increase in WEHI 78/24 binding to HEVs when compared to mice that were not inflamed (white bar; P value < 0.01). Furthermore, monocyte binding to inflamed HEVs from TNF mice was similar to that observed in uninflamed wild-type mice, analogous to what was observed in vivo. This experiment was repeated three times. (B) The ex vivo assay described previously was performed on both inflamed lymph nodes (black bars) or lymph nodes that were not inflamed (white bars) in the presence of either a MIG neutralizing antibody (anti-MIG), a control (Control Ab), or no antibody at all (No Ab). In the presence of the control antibody, there was approximately a twofold increase in monocyte binding to inflamed HEVs compared to uninflamed HEVs (P value < 0.05). This was similar to that observed in the absence of antibody. In the presence of a MIG-neutralizing antibody, however, the degree of monocyte binding to inflamed HEVs was reduced to background levels. This experiment was repeated three times.

Mentions: Local inflammation resulted in a selective increase in WEHI 78/24 binding capacity of HEVs analogous to the in vivo results. As shown in Fig. 5 A, lymph nodes from inflamed wild-type mice had a twofold increase in WEHI 78/24 binding to HEVs when compared with mice that were not inflamed. Furthermore, WEHI 78/24 binding to inflamed HEVs from TNF mice was similar to that observed in uninflamed wild-type mice, also analogous to what was observed in vivo, suggesting that this ex vivo approach offers a reasonable assay system to model the in vivo mechanism.


Tumor necrosis factor-dependent segmental control of MIG expression by high endothelial venules in inflamed lymph nodes regulates monocyte recruitment.

Janatpour MJ, Hudak S, Sathe M, Sedgwick JD, McEvoy LM - J. Exp. Med. (2001)

MIG may play a direct role in monocyte-selective recruitment in inflammation. (A) Frozen lymph node sections were incubated with cells under nonstatic, cold conditions, and the ability of the HEVs to bind WEHI 78/24 was quantitated. Data is expressed as WEHI binding relative to an internal standard. Lymph nodes from inflamed (black bars) wild-type mice had a twofold increase in WEHI 78/24 binding to HEVs when compared to mice that were not inflamed (white bar; P value < 0.01). Furthermore, monocyte binding to inflamed HEVs from TNF  mice was similar to that observed in uninflamed wild-type mice, analogous to what was observed in vivo. This experiment was repeated three times. (B) The ex vivo assay described previously was performed on both inflamed lymph nodes (black bars) or lymph nodes that were not inflamed (white bars) in the presence of either a MIG neutralizing antibody (anti-MIG), a control (Control Ab), or no antibody at all (No Ab). In the presence of the control antibody, there was approximately a twofold increase in monocyte binding to inflamed HEVs compared to uninflamed HEVs (P value < 0.05). This was similar to that observed in the absence of antibody. In the presence of a MIG-neutralizing antibody, however, the degree of monocyte binding to inflamed HEVs was reduced to background levels. This experiment was repeated three times.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2195975&req=5

fig5: MIG may play a direct role in monocyte-selective recruitment in inflammation. (A) Frozen lymph node sections were incubated with cells under nonstatic, cold conditions, and the ability of the HEVs to bind WEHI 78/24 was quantitated. Data is expressed as WEHI binding relative to an internal standard. Lymph nodes from inflamed (black bars) wild-type mice had a twofold increase in WEHI 78/24 binding to HEVs when compared to mice that were not inflamed (white bar; P value < 0.01). Furthermore, monocyte binding to inflamed HEVs from TNF mice was similar to that observed in uninflamed wild-type mice, analogous to what was observed in vivo. This experiment was repeated three times. (B) The ex vivo assay described previously was performed on both inflamed lymph nodes (black bars) or lymph nodes that were not inflamed (white bars) in the presence of either a MIG neutralizing antibody (anti-MIG), a control (Control Ab), or no antibody at all (No Ab). In the presence of the control antibody, there was approximately a twofold increase in monocyte binding to inflamed HEVs compared to uninflamed HEVs (P value < 0.05). This was similar to that observed in the absence of antibody. In the presence of a MIG-neutralizing antibody, however, the degree of monocyte binding to inflamed HEVs was reduced to background levels. This experiment was repeated three times.
Mentions: Local inflammation resulted in a selective increase in WEHI 78/24 binding capacity of HEVs analogous to the in vivo results. As shown in Fig. 5 A, lymph nodes from inflamed wild-type mice had a twofold increase in WEHI 78/24 binding to HEVs when compared with mice that were not inflamed. Furthermore, WEHI 78/24 binding to inflamed HEVs from TNF mice was similar to that observed in uninflamed wild-type mice, also analogous to what was observed in vivo, suggesting that this ex vivo approach offers a reasonable assay system to model the in vivo mechanism.

Bottom Line: Quantitative PCR analyses revealed the upregulation of many chemokines in the inflamed lymph node, including MCP-1 and MIG.HEVs did not express detectable levels of MCP-1; however, a subset of HEVs in inflamed lymph nodes in wild-type (but not tumor necrosis factor [TNF] mice) expressed MIG and this subset of HEVs preferentially supported monocyte binding.Together, these results suggest that the lymph node microenvironment can dictate the nature of molecules expressed on HEV subsets in a TNF-dependent fashion and that inflammation-induced MIG expression by HEVs can mediate monocyte recruitment.

View Article: PubMed Central - PubMed

Affiliation: DNAX Research Institute, Inc., Palo Alto, CA 94304, USA.

ABSTRACT
Monocytes recruited from the blood are key contributors to the nature of an immune response. While monocyte recruitment in a subset of immunopathologies has been well studied and largely attributed to the chemokine monocyte chemoattractant protein (MCP)-1, mechanisms mediating such recruitment to other sites of inflammation remain elusive. Here, we showed that localized inflammation resulted in an increased binding of monocytes to perifollicular high endothelial venules (HEVs) of lymph nodes draining a local inflammatory site. Quantitative PCR analyses revealed the upregulation of many chemokines in the inflamed lymph node, including MCP-1 and MIG. HEVs did not express detectable levels of MCP-1; however, a subset of HEVs in inflamed lymph nodes in wild-type (but not tumor necrosis factor [TNF] mice) expressed MIG and this subset of HEVs preferentially supported monocyte binding. Expression of CXCR3, the receptor for MIG, was detected on a small subset of peripheral blood monocytes and on a significant percentage of recruited monocytes. Most importantly, in both ex vivo and in vivo assays, neutralizing anti-MIG antibodies blocked monocyte binding to inflamed lymph node HEVs. Together, these results suggest that the lymph node microenvironment can dictate the nature of molecules expressed on HEV subsets in a TNF-dependent fashion and that inflammation-induced MIG expression by HEVs can mediate monocyte recruitment.

Show MeSH
Related in: MedlinePlus