IL-6 and IL-12 specifically regulate the expression of Rab5 and Rab7 via distinct signaling pathways.
Recent studies have shown that phagosome maturation depends on the balance between pro-inflammatory and anti-inflammatory cytokines, indicating that cytokine modulates phagosome maturation. However, the mechanism of cytokine-mediated modulation of intracellular trafficking remains to be elucidated. Here, we have shown that treatment of macrophages with IL-6 specifically induce the expression of Rab5 through the activation of extracellular signal-regulated kinase, whereas IL-12 exclusively upregulate the expression of Rab7 through the activation of p38 MAPK. We have cloned the 5'-flanking regions of the rab5c or rab7 into the promoterless reporter vector. Our results have shown that cells transfected with rab5c chimera are transactivated by IL-6, and IL-12 specifically transactivates cells containing rab7 chimera. Moreover, our results also show that IL-12 induces lysosomal transport, whereas IL-6 stimulates the fusion between early compartments in macrophages and accordingly modulates Salmonella trafficking and survival in macrophages. This is the first demonstration showing that cytokine differentially regulates endocytic trafficking by controlling the expression of appropriate Rab GTPase, and provides insight into the mechanism of cytokine-mediated regulation of intracellular trafficking.
Bhattacharya
Malavika
M
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
Ojha
Namrata
N
Solanki
Sunil
S
Mukhopadhyay
Chinmay K
CK
Madan
Richa
R
Patel
Nitin
N
Krishnamurthy
Ganga
G
Kumar
Senthil
S
Basu
Sandip K
SK
Mukhopadhyay
Amitabha
A
D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects*; D018664:Interleukin-12 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008264:Macrophages / Q000166:cytology / Q000382:microbiology; D051379:Mice; D010587:Phagocytosis / Q000187:drug effects; D010770:Phosphotransferases / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012475:Salmonella / Q000166:cytology / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*; D013379:Substrate Specificity; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000090802:rab7 GTP-Binding Proteins
D015850:Interleukin-6; D012333:RNA, Messenger; D000090802:rab7 GTP-Binding Proteins; C000716465:rab7 GTP-binding proteins, mouse; D018664:Interleukin-12; D010770:Phosphotransferases; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins