A MyD88-JAK1-STAT1 complex directly induces SOCS-1 expression in macrophages infected with Group A Streptococcus.
Some pathogens can use host suppressor of cytokine signaling 1 (SOCS-1), an important negative-feedback molecule, as the main mode of immune evasion. Here we found that group A Streptococcus (GAS) is capable of inducing SOCS-1 expression in RAW264.7 and BMDM macrophages. IFN-β plays a role in GAS-induced SOCS-1 expression in macrophages following the induction of cytokine expression by GAS, representing the classical pathway of SOCS-1 expression. However, GAS also induced STAT1 activation and SOCS-1 expression when GAS-infected cells were incubated with anti-IFN-β monoclonal antibody in this study. Moreover, upon comparing TLR4(-/-) BMDM macrophages with wild-type (WT) cells, we found that TLR4 also plays an essential role in the induction of SOCS-1. MyD88, which is an adaptor protein for TLR4, contributes to STAT1 activation and phosphorylation by forming a complex with Janus kinase 1 (JAK1) and signal transducer and activator of transcription 1 (STAT1) in macrophages. GAS-stimulated expression of STAT1 was severely impaired in MyD88(-/-) macrophages, whereas expression of JAK1 was unaffected, suggesting that MyD88 was involved in STAT1 expression and phosphorylation. Together, these data demonstrated that in addition to IFN-β signaling and MyD88 complex formation, JAK1 and STAT1 act in a novel pathway to directly induce SOCS-1 expression in GAS-infected macrophages, which may be more conducive to rapid bacterial infection.
1] Hebei Medical University, Shijiazhuang, China [2] Hebei United University Affiliated Hospital, Tangshan, China.
Jinghua
J
Wu
Hebei Medical University, Shijiazhuang, China.
Cuiqing
C
Ma
Tangshan City Hospital of Traditional Chinese Medicine, Tangshan, China.
Haixin
H
Wang
Hebei Medical University, Shijiazhuang, China.
Shuhui
S
Wu
Hebei Medical University, Shijiazhuang, China.
Gao
G
Xue
Hebei Medical University, Shijiazhuang, China.
Xinli
X
Shi
Hebei Medical University, Shijiazhuang, China.
Zhang
Z
Song
Hebei Medical University, Shijiazhuang, China.
Lin
L
Wei
D000818:Animals; D019138:Antibodies, Blocking / Q000378:metabolism; D000911:Antibodies, Monoclonal / Q000378:metabolism; D002460:Cell Line; D057131:Immune Evasion; D016899:Interferon-beta / Q000378:metabolism; D053613:Janus Kinase 1 / Q000378:metabolism; D008264:Macrophages / Q000276:immunology* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D013290:Streptococcal Infections / Q000276:immunology*; D013297:Streptococcus pyogenes / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D053594:Myeloid Differentiation Factor 88; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D053613:Janus Kinase 1