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JC Grab Bag and Misc > JAK1 and STAT3/STAT6 > Flashcards

JAK1 and STAT3/STAT6 Flashcards

1
Q

Transcription levels of which cytokines were significantly higher in lesional and nonlesional skin in CAD dogs?

A

IL4 and IL13

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2
Q

What cells infiltrate lesional CAD skin and what chemokine receptor has increased transcription?

A

CD4+ infiltrate and increased transcription of CCR4 selectively expressed on Th2 cells; canine CD4+ CCR4+ lymphocytes preferentially induced the transcription of IL4 and IL13

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3
Q

When cytokines bind to receptors, what are phosphorylated?

A

JAKs and STATs

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4
Q

What do phosphorylated STATs do?

A

Form dimers and translocate into the nucleus, affected the transcriptional regulation of DNA

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5
Q

What are the 4 JAKs and 7 STATs in mammals?

A

JAK1, JAK2, JAK3, and TYK2
STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6

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6
Q

In a human keratinocyte cell line (HaCaT cells), __________ induced the phosphorylation of ____

A

IL4 and IL13
JAK1

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7
Q

_____ and _____ were phosphorylated when activated by ____ and _____

A

STAT3 and STAT 6
IL4 and IL13

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8
Q

In the presence of IL4 and IL13, the knockout of STAT3 in NHEKs induced the transcription of what?

A

Skin barrier-forming proteins such as filaggrin and loricrin

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9
Q

The inhibition of STAT6 expression in NHEKs treated with IL4 and IL13 down regulated ______

A

CCL26, a Th2 chemokine

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10
Q

Signal transduction via STAT3 in keratinocytes is involved in?

A

Reducing barrier functions

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11
Q

Signal transduction via STAT6 in keratinocytes is involved in what?

A

Promoting inflammation

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12
Q

Phosphorylation of JAK1, STAT3, and STAT6 is a marker for what?

A

Keratinocyte activation in a Th2-dominant milieu

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13
Q

What JAKs and STATs were detected in the epidermis in human AD?

A

phospho-(p)JAK1, pSTAT3, and pSTAT6; suggests activation of JAK1, STAT3, and STAT6 in keratinocytes is associated with worsening of AD

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14
Q

What receptor was transcribed in the canine progenitor of epidermal keratinocytes (CPEKs) indicating that keratinocytes may also be activated via the JAK/STAT pathway in CAD?

A

IL13 receptor alpha (RA)1, one of the receptor chains for IL4 and IL13

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15
Q

What primary antibodies can be used for immunohistochemical analysis of JAKs and STATs?

A

rabbit polyclonal anti-pJAK1 Ab, rabbit monoclonal anti-pSTAT3 Ab, rabbit monoclonal anti-pSTAT6 Ab

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16
Q

What pathological changes are evident in lesional CAD skin?

A

epidermal hyperplasia, orthokeratotic and parakeratotic hyperkeratosis, hypergranulosis, spongiosis, melanosis or leukocyte exocytosis

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17
Q

What JAKs or STATs were observed in all CAD samples?

A

phospho-JAK1 positive keratinocytes (except for one secondary lesion)
phospho-STAT3 positive keratinocytes present in small numbers in all lesional skin (except a single secondary lesion in which a large number were detected)
(in the secondary lesion with a large number of pSTAT3 positive keratinocytes no pJAK1positive keratinocytes were detected)
Phospho-STAT6 positive keratinocytes were present in primary, secondary, and nonlesional atopic skin

18
Q

What JAKs or STATs were observed in the mononuclear cells of the dermis?

A

positive staining for pJAK1 and pSTAT6

19
Q

Which JAK or STAT had a significantly higher percentage of positive keratinocytes in primary lesions than in non-atopic healthy skin?

A

pJAK1

20
Q

Which JAK or STAT had a significantly higher percentage of positive keratinocytes in BOTH primary AND secondary lesions than in non-atopic healthy skin?

A

pSTAT6

21
Q

Which JAK or STAT had NO difference amongst healthy or atopic skin?

A

pSTAT3

22
Q

What is the significance of phosphorylation of JAK1 in lesional skin of CAD dogs?

A

JAK1 is an intracellular signaling pathway induced by IL4 and IL13, presence provides direct evidence of the activation of lesional keratinocytes by Th2 cytokines

23
Q

Which cytokines and chemokines are examples of the essential role of keratinocytes?

A

TSLP and CCL17

24
Q

The transcription levels of TSLP were significantly ______ in lesional and nonlesional skin of CAD than healthy skin.

A

higher

25
Q

CCL17 promotes T cell migration and was/was not detected in the lesions of CAD

A

WAS

26
Q

Soluble factors like TSLP and CCL17 in keratinocytes may be regulated by __________

A

Th2 cytokines

27
Q

Transcription of which receptor for IL4 and IL13 was reported previously in CPEKs suggesting that JAK could be phosphorylated in the keratinocytes of CAD upon activation with IL4 and IL13?

A

IL-13RA1

28
Q

pJAK1 positive keratinocytes had a significantly higher percentage in _______ lesions and also was detected in nonlesional skin

A

primary
the number of pJAK1 positive keratinocytes was slightly lower in secondary lesions than primary lesions (not detected in 1 secondary lesion)

29
Q

pSTAT6 was noted in ________ lesions, including lesions where pJAK1 was absent

A

secondary

30
Q

pSTAT6 is activated only by?

A

IL4 and IL13, pSTAT6 may indicate prior activation of keratinocytes

31
Q

Does oclacitinib affect keratinocyte function?

A

No reports of that but detection of pJAK1 in keratinocytes in CAD suggests that it may also have therapeutic effectiveness in blocking both keratinocyte and T-cell activation

32
Q

IL22 induces what in the chronic phase of AD?

A

acanthosis

33
Q

The transcription level of IL22 was increased in secondary lesions with lichenification in which pSTAT3 was detected in a mouse model. How does that correlate with dogs?

A

secondary lesions with a large number of pSTAT3 positive keratinocytes showed a thickened epidermis therefor the phosphorylation of STAT3 may have been induced by IL22 in CAD

34
Q

Phospho-STAT3 positive keratinocytes were detected in _______ secondary lesions.

A

only one; in NHEKs, STAT3 was phosphorylated when stimulated by IL4 and IL13, and not only Th2 cytokines but also IL22

35
Q

T/F The phosphorylation of STATs in CAD appears to be limited to either STAT3 or STAT6, but not both.

A

True, all negative samples for pSTAT3 show an increased number of pSTAT6 positive keratinocytes

36
Q

In HaCaT cells, IL4 and IL13 unregulated the transcription of suppressor of cytokine signaling _____ and ______ via STAT6.

A

SOCS-1 and SOCS-3

37
Q

Phospho-STAT6 was detected in which samples?
pSTAT6 keratinocytes were significantly higher in which samples?

A

lesional, nonlesional AD, and healthy skin
primary and secondary lesional CAD than in healthy skin

38
Q

In HaCaT cells, IL4 suppressed the transcription of which barrier-forming protein?

A

inovlucrin, this inhibition was ameliorated by a pan-JAK inhibitor or the knockout of STAT6 suggesting that the production of involucrin is regulated by IL4 by the JAK/STAT6 pathway

39
Q

In NHEKs stimulated by IL13 the knockout of STAT6 inhibited the transcription of what protein involved in the chronicity of AD?

A

periostin, in CPEKs IL13 enhanced the transcription

40
Q

Keratinocytes in CAD could be activated by the JAK1-to-STAT6 signaling pathway in the presence of ___________, which may exacerbate CAD by reducing barrier function and promoting chronic allergic inflammation.

A

IL4 and IL13

41
Q

In a mouse model of AD, _____ inhibitors significantly reduced skin lesions.

A

STAT6, because STAT6 is located downstream of JAK1, STAT6 inhibitors may be effective in CAD

42
Q

Activation of keratinocytes as demonstrated by the phosphorylation of _________ in lesional and nonlesional CAD skin.

A

JAK1/STATs

JC Grab Bag and Misc (13 decks)

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