Interleukin-32α production is regulated by MyD88-dependent and independent pathways in IL-1β-stimulated human alveolar epithelial cells.
Interleukin (IL)-32 is a recently described cytokine that appears to play a critical role in a variety of inflammatory diseases including chronic obstructive pulmonary disease (COPD). However, thus far, the regulation of IL-32 production has not been fully established. Here, we report on signaling pathways that regulate the production of IL-32α, the most abundant isoform, in the human alveolar epithelial cell line, A549. IL-32α was expressed and secreted by IL-1β. The IL-32 expression was attenuated by PP2 (a Src-family kinase [SFK] inhibitor), rottlerin (a protein kinase [PK] Cδ inhibitor), and LY294002 (a phosphatidylinositol 3-kinase [PI3K] inhibitor). Furthermore, the overexpression of Fgr rather than other SFKs upregulated IL-32α expression, while Fgr small interfering RNA (siRNA) transfection downregulated it. The suppression of Fgr with PP2 and Fgr siRNA inhibited activating phosphorylation of PKCδ and PI3K/Akt, but not IL-1 receptor-associated kinase (IRAK)1, a well-known MyD88-dependent signaling molecule, and Erk1/2, p38, and JNK. Rottlerin and PKCδ siRNA also inhibited expression of IL-32α and activation of PI3K/Akt, but not of IRAK1 and mitogen activation protein (MAP) kinases. MyD88 siRNA suppressed the expression of IL-32α and the phosphorylation of IRAK1, PI3K, and MAP kinases, but not of PKCδ. Of interest, both Fgr/PKCδ and MyD88-dependent signals regulated PI3K/Akt, suggesting that it is a crosstalk molecule. Among MyD88-dependent MAP kinases, only p38 regulated IL-32α expression and PI3K/Akt activation. With these results, we demonstrated that the expression and secretion of IL-32α are regulated by MyD88-dependent IRAK1/p38/PI3K and independent Fgr/PKCδ/PI3K pathways, and that Fgr and PKCδ are critical for the MyD88-independent IL-32α production.
Ko
Na Young
NY
College of Medicine, Konkuk University, Chungju 380-701, Republic of Korea.
Mun
Se Hwan
SH
Lee
Seung Hyun
SH
Kim
Jie Wan
JW
Kim
Do Kyun
DK
Kim
Hyuk Soon
HS
Her
Erk
E
Kim
Soo Hyun
SH
Won
Hyung Sik
HS
Shin
Hwa Sup
HS
Kim
Hyung Sik
HS
Kim
Young Mi
YM
Choi
Wahn Soo
WS
D000098:Acetophenones / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051745:Protein Kinase C-delta / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011650:Pulmonary Alveoli / Q000473:pathology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019076:Transgenes / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C412373:AG 1879; D000098:Acetophenones; D001578:Benzopyrans; D002867:Chromones; C496971:IL32 protein, human; D053583:Interleukin-1beta; D007378:Interleukins; D009025:Morpholines; D053594:Myeloid Differentiation Factor 88; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D034741:RNA, Small Interfering; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C085746:rottlerin; C053102:proto-oncogene proteins c-fgr; D019061:src-Family Kinases; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases; D051745:Protein Kinase C-delta