PMID- 18454155
OWN - NLM
STAT- MEDLINE
DCOM- 20080717
LR  - 20221109
IS  - 1546-170X (Electronic)
IS  - 1078-8956 (Print)
IS  - 1078-8956 (Linking)
VI  - 14
IP  - 5
DP  - 2008 May
TI  - Activation of c-Kit in dendritic cells regulates T helper cell differentiation 
      and allergic asthma.
PG  - 565-73
LID - 10.1038/nm1766 [doi]
AB  - Dendritic cells (DCs) are integral to the differentiation of T helper cells into 
      T helper type 1 T(H)1, T(H)2 and T(H)17 subsets. Interleukin-6 (IL-6) plays an 
      important part in regulating these three arms of the immune response by limiting 
      the T(H)1 response and promoting the T(H)2 and T(H)17 responses. In this study, 
      we investigated pathways in DCs that promote IL-6 production. We show that the 
      allergen house dust mite (HDM) or the mucosal adjuvant cholera toxin promotes 
      cell surface expression of c-Kit and its ligand, stem cell factor (SCF), on DCs. 
      This dual upregulation of c-Kit and SCF results in sustained signaling downstream 
      of c-Kit, promoting IL-6 secretion. Intranasal administration of antigen into 
      c-Kit-mutant mice or neutralization of IL-6 in cultures established from the 
      lung-draining lymph nodes of immunized wild-type mice blunted the T(H)2 and 
      T(H)17 responses. DCs lacking functional c-Kit or those unable to express 
      membrane-bound SCF secreted lower amounts of IL-6 in response to HDM or cholera 
      toxin. DCs expressing nonfunctional c-Kit were unable to induce a robust T(H)2 or 
      T(H)17 response and elicited diminished allergic airway inflammation when 
      adoptively transferred into mice. Expression of the Notch ligand Jagged-2, which 
      has been associated with T(H)2 differentiation, was blunted in DCs from 
      c-Kit-mutant mice. c-Kit upregulation was specifically induced by T(H)2- and 
      T(H)17-skewing stimuli, as the T(H)1-inducing adjuvant, CpG oligodeoxynucleotide, 
      did not promote either c-Kit or Jagged-2 expression. DCs generated from mice 
      expressing a catalytically inactive form of the p110delta subunit of 
      phosphatidylinositol-3 (PI3) kinase (p110(D910A)) secreted lower amounts of IL-6 
      upon stimulation with cholera toxin. Collectively, these results highlight the 
      importance of the c-Kit-PI3 kinase-IL-6 signaling axis in DCs in regulating T 
      cell responses.
FAU - Krishnamoorthy, Nandini
AU  - Krishnamoorthy N
AD  - Division of Pulmonary, Allergy and Critical Care Medicine, Department of 
      Medicine, University of Pittsburgh School of Medicine, 3459 Fifth Avenue, 
      Pittsburgh, Pennsylvania 15213, USA.
FAU - Oriss, Timothy B
AU  - Oriss TB
FAU - Paglia, Melissa
AU  - Paglia M
FAU - Fei, Mingjian
AU  - Fei M
FAU - Yarlagadda, Manohar
AU  - Yarlagadda M
FAU - Vanhaesebroeck, Bart
AU  - Vanhaesebroeck B
FAU - Ray, Anuradha
AU  - Ray A
FAU - Ray, Prabir
AU  - Ray P
LA  - eng
SI  - GEO/GSE10815
GR  - R01 HL077430/HL/NHLBI NIH HHS/United States
GR  - HL 060207/HL/NHLBI NIH HHS/United States
GR  - AI 048927/AI/NIAID NIH HHS/United States
GR  - HL 084932/HL/NHLBI NIH HHS/United States
GR  - HL 077430/HL/NHLBI NIH HHS/United States
GR  - P50 HL084932/HL/NHLBI NIH HHS/United States
GR  - HL 069810/HL/NHLBI NIH HHS/United States
GR  - R01 HL069810/HL/NHLBI NIH HHS/United States
GR  - R01 HL060207/HL/NHLBI NIH HHS/United States
GR  - R01 AI048927/AI/NIAID NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20080504
PL  - United States
TA  - Nat Med
JT  - Nature medicine
JID - 9502015
RN  - 0 (Antigens, Dermatophagoides)
RN  - 0 (Interleukin-6)
RN  - 9012-63-9 (Cholera Toxin)
RN  - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit)
SB  - IM
CIN - Nat Med. 2008 May;14(5):487-8. PMID: 18463654
MH  - Adoptive Transfer
MH  - Animals
MH  - Antigens, Dermatophagoides/immunology
MH  - Asthma/*immunology
MH  - Cell Differentiation/*immunology
MH  - Cholera Toxin/immunology
MH  - Dendritic Cells/*metabolism
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Flow Cytometry
MH  - Gene Expression Regulation/*immunology
MH  - Interleukin-6/genetics/*immunology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Microarray Analysis
MH  - Microscopy, Fluorescence
MH  - Proto-Oncogene Proteins c-kit/*metabolism
MH  - T-Lymphocytes, Helper-Inducer/*cytology
PMC - PMC3664066
MID - NIHMS460401
COIS- Competing interests statement: The authors declare no competing financial 
      interests.
EDAT- 2008/05/06 09:00
MHDA- 2008/07/18 09:00
PMCR- 2013/05/25
CRDT- 2008/05/06 09:00
PHST- 2007/09/14 00:00 [received]
PHST- 2008/03/26 00:00 [accepted]
PHST- 2008/05/06 09:00 [pubmed]
PHST- 2008/07/18 09:00 [medline]
PHST- 2008/05/06 09:00 [entrez]
PHST- 2013/05/25 00:00 [pmc-release]
AID - nm1766 [pii]
AID - 10.1038/nm1766 [doi]
PST - ppublish
SO  - Nat Med. 2008 May;14(5):565-73. doi: 10.1038/nm1766. Epub 2008 May 4.