Differential expression and cross-regulatory function of RANTES during mycobacterial (type 1) and schistosomal (type 2) antigen-elicited granulomatous inflammation.
The role of RANTES in Th1 and Th2 cell-mediated immune responses has been enigmatic. To approach this question, we analyzed RANTES expression and function in murine models of types 1 and 2 cell-mediated pulmonary granulomas elicited with Mycobacterium bovis or Schistosoma mansoni egg Ag-coated beads, respectively. Compared with type 2, type 1 lesions had up to 4-fold greater RANTES protein and mRNA production. Type 1 draining lymph nodes also produced up to 7-fold higher levels of RANTES. Anti-RANTES Ab treatments had opposite effects, decreasing type 1 lesion area by 25% and augmenting type 2 lesions by 50%. The latter was associated with increased IL-4, IL-5, IL-10, and IL-13 production by lymph nodes. Infusion of rRANTES (1 mg/kg/day) did not affect type 1 lesions, but reduced type 2 lesion area by 27% and eosinophils by 40%. Lymph node cultures from RANTES-treated mice had augmented type 1 and impaired type 2 responses. In vitro, RANTES caused selective, dose-related inhibition of IL-4 that was largely dependent on CCR1 receptors. In conclusion, RANTES plays different roles in types 1 and 2 granuloma formation, promoting the former and mediating cross-regulatory inhibition of the latter. Moreover, RANTES may have therapeutic potential in the treatment of established type 2 hypersensitivity.
Chensue
S W
SW
Department of Pathology, Veterans Affairs Medical Center, University of Michigan Medical School, Ann Arbor 48105, USA.
Warmington
K S
KS
Allenspach
E J
EJ
Lu
B
B
Gerard
C
C
Kunkel
S L
SL
Lukacs
N W
NW
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D000947:Antigens, Helminth / Q000276:immunology*; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D015769:Granuloma, Respiratory Tract / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007106:Immune Sera / Q000008:administration & dosage / Q000494:pharmacology; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology; D015918:Infusion Pumps, Implantable; D015847:Interleukin-4 / Q000096:biosynthesis; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000276:immunology; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000502:physiology; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000473:pathology / Q000628:therapy
D000276:Adjuvants, Immunologic; D000942:Antigens, Bacterial; D000947:Antigens, Helminth; C515301:Ccr1 protein, mouse; D018946:Chemokine CCL5; D016207:Cytokines; D007106:Immune Sera; D007074:Immunoglobulin G; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D015847:Interleukin-4