Essential role of Stat5 for IL-5-dependent IgH switch recombination in mouse B cells.
IL-5 stimulation of CD38-activated murine splenic B cells induces mu-gamma1 CSR at the DNA level leading to a high level of IgG1 production. Further addition of IL-4 in the system enhances IL-5-dependent mu-gamma1 CSR. Although some of the postreceptor signaling events initiated by IL-5 in activated B cells have been characterized, the involvement of Stat in IL-5 signaling has not been thoroughly evaluated. In this study, we examined the activation of Stat5 and activation-induced cytidine deaminase (AID) in CD38-activated murine splenic B cells by IL-5. The role of Stat5a and Stat5b in IL-5-induced mu-gamma1 CSR and also IgG1 and IgM production was documented, as IL-5 does not act on CD38-stimulated splenic B cells from Stat5a(-/-) and Stat5b(-/-) mice. Expression levels of CD38-induced germline gamma1 transcripts and AID in Stat5a(-/-) and Stat5b(-/-) B cells upon IL-5 stimulation were comparable to those of wild-type B cells. The impaired mu-gamma1 CSR by Stat5b(-/-) B cells, but not by Stat5a(-/-) B cells, was rescued in part by IL-4, as the addition of IL-4 to the culture of CD38- and IL-5-stimulated B cells induced mu-gamma1 CSR leading to IgG1 production. Analysis of cell division cycle number of wild-type B cells revealed that mu-gamma1 CSR was observed after five or six cell divisions. Stat5a(-/-) and Stat5b(-/-) B cells showed similar cell division cycles, but they did not undergo mu-gamma1 CSR. Our data support the notion that both Stat5a and Stat5b are essential for IL-5-dependent mu;-gamma1 CSR and Ig secretion; however, their major target may not be AID. Stat5a and Stat5b are not redundant, but rather are at least partially distinctive in their function.
Horikawa
K
K
Department of Immunology, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
Kaku
H
H
Nakajima
H
H
Davey
H W
HW
Hennighausen
L
L
Iwamoto
I
I
Yasue
T
T
Kariyone
A
A
Takatsu
K
K
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism*; D003564:Cytidine Deaminase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis*; D007075:Immunoglobulin M / Q000096:biosynthesis* / Q000235:genetics; D015848:Interleukin-5 / Q000494:pharmacology*; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008894:Milk Proteins; D009244:NAD+ Nucleosidase / Q000494:pharmacology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012333:RNA, Messenger / Q000032:analysis; D011995:Recombination, Genetic; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis
D015703:Antigens, CD; D000943:Antigens, Differentiation; D004268:DNA-Binding Proteins; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007075:Immunoglobulin M; D015848:Interleukin-5; D008562:Membrane Glycoproteins; D008894:Milk Proteins; C513258:Prdm1 protein, mouse; D012333:RNA, Messenger; D012097:Repressor Proteins; D050799:STAT5 Transcription Factor; C494093:Stat5a protein, mouse; C494096:Stat5b protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D003564:Cytidine Deaminase