Microvascular expression of MALA-2 correlates with in vivo lymphocyte trafficking and is preferentially enhanced in tumors by tumor necrosis factor-alpha and interleukin-1 alpha.
The role of endothelial cell adhesion molecule expression in the immune response to tumors is unknown. We have investigated the expression of murine lymphocyte activation antigen (MALA-2), the murine equivalent of intercellular adhesion molecule-1 (ICAM-1), in blood vessels of normal murine tissues and in melanoma tumors and evaluated the relationship between MALA-2 expression and lymphocyte trafficking in vivo. C3H/HeN mice were injected both i.p. and s.c. with a clone of K-1735 syngeneic melanoma cells. Day 11 tumor-bearing mice were killed and vascular expression of MALA-2 was quantified using immunohistochemistry. MALA-2 expression was high in lung, liver and spleen and low in lymph node, small bowel, muscle and tumor. Systemic administration of either recombinant tumor necrosis factor alpha (rTNF alpha) or recombinant interleukin-1 alpha (rIL-1 alpha) over 2 days prior to organ harvest resulted in an increase in the number of tumor vessels expressing MALA-2, with no change in MALA-2 expression in other tissues. In vivo lymphocyte trafficking was evaluated using cultured, activated splenocytes radiolabeled with 111In. 111In-labeled splenocyte distribution correlated closely with MALA-2 expression, with high localization to spleen, liver and lung and poor localization to lymph node, small bowel, muscle and tumor. Systemic administration of rTNF alpha, but not rIL-1 alpha, resulted in a significant increase in 111In-labeled splenocyte distribution to tumor, but neither rTNF alpha nor IL-1 alpha altered 111In-labeled splenocyte distribution to normal organs. Our data demonstrate the in vivo pattern of vascular MALA-2 expression in normal murine tissues and tumors and suggest that the expression of MALA-2 can be preferentially enhanced in tumors by systemic administration of cytokines. Lymphocyte distribution in vivo correlates closely with the pattern of MALA-2 expression, and these data support the conclusion that MALA-2 plays an important role in the regulation of lymphocyte trafficking.
Dean
P A
PA
Department of Surgery, Mayo Clinic, Rochester, MN.
Ramsey
P S
PS
Donohue
J H
JH
Nelson
H
H
D000818:Animals; D000911:Antibodies, Monoclonal; D005260:Female; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis*; D007375:Interleukin-1 / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology*; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000737:chemistry / Q000276:immunology; D051379:Mice; D008809:Mice, Inbred C3H; D008833:Microcirculation / Q000378:metabolism*; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000494:pharmacology; D013154:Spleen / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000911:Antibodies, Monoclonal; C090509:Icam1 protein, mouse; D007375:Interleukin-1; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1