Table 1 Mechanism and function of BRDs in immunity and disease

BRD2

BRD4

N/A

Gram-negative bacterial infection

Mouse SIM-A9 microglial cell line, mouse primary astrocytes

LPS

N/A

N/A

NOS2, COX2, IL1B, TNF, IL6, CCL2, MMP9, SERPINE1

dBET1, JQ1

^46,131

BRD2 BRD3 BRD4

N/A

Endotoxemia

Mouse bone marrow derived macrophages (BMDMs)

LPS

RELA, IRF4, IRF8

H3Ac, H4K5Ac, H4K8Ac, H4K12Ac, H4Ac

TNF, IL6, IFNB1, CCL2, IL1B, IL12A, CXCL9, CCL12

I-BET, JQ1

⁶⁹

BRD4

N/A

Sepsis, group B Streptococcus (GBS) infection

Mouse BMDMs

GBS, LPS, cecal ligation puncture

RELA

N/A

IL6, IL1A, IL12B, CXCL9, IL23A

N/A

⁹⁷

BRD2

BRD4

Upregulation

Pseudomonas aeruginos infection

Human bronchial epithelial cells

IL17

N/A

N/A

IL17A, IL22, CXCL1, CXCL5, CXCL8, CCL2, CSF3, IL6

CPI-203

¹⁸⁶

BRD2 BRD3 BRD4

N/A

Heat-killed L. monocytogenes infection

Mouse BMDMs

IFNB

RELA

N/A

NOS2, IL6, IL1RN

JQ1

⁹⁴

BRD4

Upregulation

RNA virus (respiratory syncytial virus infection)

Human small airway epithelial cells, nonciliated secretoglobin (Scgb1a1)-expressing bronchiolar epithelial cells

Poly(I:C)

RELA, IRF1, IRF7, IRF3

H3K122Ac

IL6, ISG54, CIG5, RANTES, FN1, COL1A, MMP9, VIM, ACTA2, HEXIM1, KC, CSF3, CSF2, CXCL1, CXCL2, CXCL8, CCL2

ZL0513, ZL0516, ZL0420, ZL0454, JQ1

^{55,56,57,58,110,187}

BRD4

No change

Virus infection

Pig PK15 cells

Pseudorabies virus, herpes simplex virus, ectromelia virus, etc.

IRF3, RELA

H3K9, H3K27, H4K8, H4K12, H4K16

IL1B, IFNB, ISG15

JQ1, OTX-015, I-BET 151

³⁹

BRD4

Downregulation

HIV-1 infection

Memory CD4+ T cells

N/A

N/A

N/A

N/A

N/A

³⁸

BRD4

N/A

HIV-1 infection

J-Lat A2 cell line

N/A

N/A

N/A

HIV

JQ1

¹⁰⁷

BRD3

Downregulation

Virus infection

Mouse macrophage cell line RAW 264.7

Sendai virus, vesicular stomatitis virus, herpes simplex virus

IRF3

H3/H4

IFNB1

N/A

⁵⁰

BRD2

BRD3 BRD4

N/A

Candida albicans and Aspergillus fumigatus infection

Whole blood

cells, peripheral blood mononuclear cells, monocytes

N/A

N/A

H3K4Me3, H3K27Ac

TNF, IL6

I-BET151, JQ1

¹²⁹

BRD2

Upregulation

Plasmodium yoelii and Toxoplasma gondii-infected liver

N/A

N/A

N/A

N/A

TNF, IFNG

N/A

¹⁴⁰

BRD2

BRD3 BRD4

N/A

Schistosoma japonicum infection

Human Th17 cells

N/A

RORC

N/A

IL17, IL21, CSF2

JQ1

¹⁴¹

BRD4

Upregulation

Renal cancer

Human renal cell carcinoma cell lines

LPS

RELA

H3K27Ac

CXCL1, CXCL8, CXCR2, CSF2, CSF3, NLRP3

JQ1

^33,148

BRD4

N/A

Prostate cancer

Human prostate cancer cell lines (DU145, PC3)

N/A

N/A

N/A

CD274, HLA-A, HLA-C, IFNG

JQ1

¹⁵²

BRD4

N/A

Pancreatic cancer

Pancreatic cancer cell lines (PANC-1, BxPC-3, MIA PaCa-2), pancreatic stellate cells

IFNG

IRF1

N/A

CD274

JQ1, IBET

^153,154

BRD2

BRD3

BRD4

N/A

Pancreatic cancer

Aspc-1, PANC-1, CAPAN-1 cells, mouse pancreatic cancer cell lines PanAsc 2159 and Panc 1343, RAW 264.7

IFNG, LPS

STAT3

N/A

IL6, CCL2, CSF2

JQ1, I-BET 762

^35,102

BRD3

N/A

Gastric adenocarcinoma

Microsatellite instability high gastric cancer cells

N/A

N/A

N/A

CD274

N/A

⁴⁶

BRD2

BRD3

BRD4

N/A

A549 tumor-bearing nude mice, neuroblastoma

N/A

N/A

N/A

N/A

CD274

JQ1

¹⁵⁵

BRD4

N/A

Triple-negative breast cancer, hepatocellular carcinoma

Peripheral blood mononuclear cells, monocytes

N/A

CEBPB

H3K27Ac

CD274

JQ1, I-BET762

^115,156

BRD4

N/A

Triple-negative breast cancer

Human breast cancer cell line

IL6

N/A

N/A

JAG1

JQ1

¹⁴⁷

BRD2

BRD4

Upregulation

Malignant pleural mesothelioma

Human primary malignant pleural mesothelioma cells

N/A

N/A

N/A

CD274, PDCD1

JQ1, OTX015

³⁴

BRD2

N/A

Melanoma

Human melanoma cell lines (Mel-RMu, SK-Mel28, Mel-RM, Mel-JD, Me1007)

N/A

RELA

N/A

IL6, IL8, VEGF, CXCL10, RANTES

I-BET151

⁸⁷

BRD2

BRD3

BRD4

N/A

Human Ty-82 xenografts

Ty-82, SKOV3, A549, MDA-MB-231 cells

N/A

N/A

H3K27Ac

IDO1

ABBV-075, JQ1, OTX015

¹²⁶

BRD4

Upregulation

Breast cancer

with T-bet+ tumor-infiltrating T lymphocytes

T-bet+ TILs

N/A

N/A

N/A

JAG1

N/A

¹⁴⁹

BRD4

Upregulation

Mucoepidermoid carcinoma

Human mucoepidermoid carcinoma cells

N/A

RELA

N/A

N/A

I-BET762

³⁷

BRD2

BRD3

BRD4

N/A

Neuroblastoma

NK cells

N/A

MYC, TP53

N/A

ULBP1, ULBP3, PVR, NECTIN2

JQ1

¹⁸⁸

BRD2 BRD3 BRD4

N/A

Primary effusion lymphoma

N/A

N/A

RELA

N/A

IL6

JQ1

¹⁸⁹

BRD2

BRD3 BRD4

N/A

Myeloproliferative neoplasms

JAK2V617F-positive SET-2 cells

N/A

RELA

H3K27Ac

CCL2, CCL3, CCL4, CCL5, IL10, IL6, IL13, CXCL9, CSF3, II15, CXCL10, II1A, CXCL2, CXCL5

JQ1

⁶¹

BRD4

N/A

Multiple myeloma

Human myeloma cell lines (SKO-007(J3), U266, ARP-1, RPMI-8226), human multiple myeloma cell line (JJN-3)

N/A

MYC

N/A

MICA

ARV-825 (PROTAC), JQ1, I-BET151

¹³³

BRD4

Upregulation

Pathological cardiac hypertrophy

Neonatal mouse cardiomyocytes

Aortic banding, angiotensin-II

RELA

N/A

TNF, IL1B

N/A

¹⁵⁸

BRD4

Upregulation

Pulmonary arterial hypertension

Human microvascular endothelial cells, smooth muscle cells

N/A

FOXM1

N/A

FOXM1, PLK1, IL8, MCP1, CCL5

RVX208

¹⁵⁹

BRD2 BRD3

BRD4

N/A

Pulmonary arterial hypertension

Human pulmonary microvascular endothelial cells

N/A

RELA

N/A

IL6, IL8

JQ1

⁶²

BRD2 BRD3 BRD4

N/A

Cardiovascular disease

Human monocytic cell line (THP-1), human umbilical vein vessel endothelial cells, human artery endothelial cells

TNF, LPS, IL1B

RELA

N/A

VCAM1, CCL2, IL8, SELE, IL1B

Apabetalone, MZ-1

¹³²

BRD2 BRD3 BRD4

N/A

Vascular

inflammation

Human umbilical vein vessel endothelial cells

TNF, LPS

RELA

N/A

ICAM1, VCAM1, SELE

JQ1

¹³

BRD4

Upregulation

Hypertension

Rat vascular smooth muscle cells

Angiotensin II

JUN, RELA, STAT1, CDX2, FOXL1, LIN54, ETS1

H3K27Ac

ESM1, SPRY2, TGIF1, FST, FGF2, EGR2, FLT, FOXP1

JQ1

¹⁹⁰

BRD2 BRD3 BRD4

N/A

Heart failure (prolonged pressure overload, massive anterior myocardial infarction)

Human induced pluripotent stem cell-derived cardiomyocytes

ET1

RELA, JUN, STAT1

N/A

NPPB, CTGF

JQ1

¹⁰¹

BRD2 BRD4

Upregulation

Acute myocardial infarction

N/A

N/A

N/A

N/A

TLR4, TRAF6, RELA, CRP, IL6

JQ1

⁶⁶

BRD4

N/A

Atherogenesis

Human umbilical vein vessel endothelial cells

TNF

RELA

H3K27Ac

VCAM1, SOX18, CCL2

JQ1

⁶³

BRD4

Upregulation

Chronic obstructive pulmonary disorder

Human pulmonary microvascular endothelial cells

Cigarette smoke extract

N/A

N/A

IL6, IL8, TNF

N/A

^29,30

BRD2 BRD3 BRD4

No change

Chronic obstructive pulmonary disorder

Alveolar macrophages

LPS

N/A

N/A

IL6, CSF2

JQ1

⁴⁰

BRD4

N/A

Asthma

Primary human small airway epithelial cells

Cat dander extract

RELA

H3K122Ac

COL1, FN1, ZEB1, SNAI1, VIM, IL6

ZL0454

¹⁶³

BRD2 BRD3 BRD4

N/A

Asthma

CD4+ T cells, human bronchial epithelial cells

Cockroach allergen extract

N/A

N/A

IL4, IL17A, RORC, IL23R

JQ1

¹⁹¹

BRD4

N/A

Asthma

Asthmatic airway smooth muscle cells

FCS, TGFB

N/A

N/A

IL6, IL8

JQ1, I-BET762

¹⁹²

BRD2 BRD3 BRD4

N/A

Neutrophil-dominant allergic airway disease

CD4 + CD62L + naïve T cells

IL23, TGFβ, IL6, anti-IL4, anti-IFNG

N/A

N/A

IL1A, IL1B, IL2, IL6, IL10, IL12B, IL13, IL17A, CCL11, CSF3, CXCL1, CCL4, CCL5

CPI-203

¹⁹³

BRD4

N/A

Pulmonary fibrosis

Lung fibroblasts

Bleomycin

N/A

H4K5Ac

IL6

JQ1

¹²⁴

BRD2

Upregulation

Parkinson’s disease

Mouse primary microglial cells

Alpha-synuclein (αSynAgg)

STAT3

N/A

ACOD1, IFIT1, PYHIN, CDC123, SOD1, GRN

N/A

⁴⁴

BRD2 BRD3 BRD4

N/A

Systemic sclerosis

Human monocytes of systemic sclerosis patients

N/A

STAT1, STAT2, IRF

H3K27Ac

MX1, CMPK2

JQ1

¹⁰⁹

BRD4

Upregulation

Cerebral ischemia/reperfusion injury

Mouse astrocytes, microglial BV2 cells

Oxygen-glucose deprivation/reperfusion

RELA

N/A

IL6, IL1B, IL18, TNF

JQ1

⁷⁵

BRD2 BRD3 BRD4

N/A

Spinal cord injury

BMDMs

LPS

N/A

N/A

IL6, IL1B, TNF, IL4, IL13

JQ1

¹⁶⁶

BRD2 BRD3 BRD4

No change

Spinal cord injury

Primary cerebellar granule neurons, astrocytes, oligodendrocytes, microglias

IL1B, TNF

N/A

N/A

IL6, IL1B, CCL5, CCL2, CXCL10, TNF

JQ1

⁴¹

BRD2

Upregulation

Neuronal damage after deep hypothermic

circulatory arrest

Mouse microglial BV2 cells, human neuroblastoma SH-SY5Y cells

Oxygen-glucose deprivation

RELA

N/A

TNF, IL5, IL10, IL13

JQ1

⁸⁸

BRD2 BRD3 BRD4

N/A

Autoimmune encephalomyelitis

N/A

N/A

N/A

N/A

IL6, IL17, CCL2, CSF2, IFNG, TNF

RVX-297

¹⁹⁴

BRD2 BRD3 BRD4

N/A

Alzheimer’s disease

N/A

N/A

N/A

N/A

IL1B, IL6, TNF, CCL2, NOS2, PTGS2

JQ1

¹⁶⁵

BRD4

N/A

Experimental renal damage

Human renal proximal tubular epithelial cells (HK2)

Nephrotoxic serum, TNF

RELA

N/A

IL6, CCL2, CCL5

JQ1

⁹⁵

BRD2 BRD3 BRD4

N/A

Stage 4 or 5 chronic kidney disease

N/A

N/A

N/A

N/A

IL6, PAI1, OPN

Apabetalone

¹⁴

BRD4

Upregulation

Lupus nephritis

N/A

N/A

N/A

N/A

IL1B, IL6, IL17, IL10, INFG

JQ1

¹⁶⁸

BRD4

N/A

HIV-associated kidney disease

Human primary renal tubular epithelial cells

TNF, HIV

RELA

H3K9Ac, H3K18Ac, H3K4me3, H3K27me3

IL1A, IL1B, LTA, LTB, CCL2, CCL3, CCL20, CXCL3, CXCL11, CCL2, CCL20, IL8

MS417

¹⁶⁷

BRD4

Upregulation

Acute liver

injury

Mouse Kupffer cells

Listeriolysin-O

RELA

TNF, IL6, IL1B, IL18, CCL2, CCL8

JQ1

¹³⁶

BRD4

N/A

Colitis

Mouse intestinal epithelial cells

Dextran sulfate sodium

RELA

H3K9Ac

TNF, IL1B

N/A

¹⁶⁹

BRD4

N/A

Colitis

Th17 cells

N/A

N/A

H4K5Ac, H4K8Ac

IL17, IFNG, IL21, IL22, RORC, TBX21, IL6, GATA3

MS402

²⁰

BRD2 BRD3 BRD4

N/A

Colitis

Mouse BMDCs, human monocyte-derived DCs

LPS

N/A

N/A

IL6, IL12B, IL10

I-BET151

¹⁹⁵

BRD2 BRD3 BRD4

N/A

Non-alcoholic fatty liver disease, liver fibrosis

N/A

N/A

N/A

N/A

IFNG, CCL2, TNF, RSAD2, LY6A, CD4, CD7, CXCL10, STAT1, CCL5

I-BET151

¹⁰⁰

BRD2 BRD3 BRD4

N/A

Acute pancreatitis

N/A

N/A

N/A

N/A

IL6, IL10, CCL2, CXCL1

I-BET762

¹⁷⁰

BRD2 BRD4

N/A

Cancer cachexia

N/A

N/A

FOXO3

N/A

IL6, TNF, IL1B, PTHLH

JQ1

¹⁷⁴

BRD2 BRD4

N/A

Obesity, insulin resistance, diabetes

INS-1 cells, mouse adipocytes (3T3-L1)

TNF

PPARG, RELA

N/A

INS, TNF, CXCL2, IL1B, IL6, CCL2

JQ1

^24,89,172

BRD2 BRD3 BRD4

N/A

Type 1 diabetes

Pancreatic macrophages, β cells

LPS

RELA

N/A

CCL2, CCL5, CXCL1, CXCL2, IFNB1, IL1A, IL1B, NFKBIA, TNF, TNFAIP3, TNFRSF9, VCAM1, CXCL9, IL12B, IL6, MX1, MX2, RSAD2

I-BET151

¹⁷¹

BRD4

Upregulation

Intervertebral disc degeneration

Nucleus pulposus cells

TNF, advanced glycation

end products

RELA

N/A

NLRP3, CASP1, MMP13

JQ1

^28,89

BRD4

N/A

Acute gouty arthritis

Human monocytic cell line (THP-1)

Monosodium urate

RELA

N/A

IL1B

Benzo[cd]indol-2(1H)-ones, Pyrrolo[4,3,2-

dequinolin-2(1H)-ones

⁷⁴

BRD4

Upregulation

Periprosthetic osteolysis

Mouse macrophage RAW264.7 cells

Titanium particles

RELA

N/A

TNF, IL1B, IL6

JQ1

¹⁹⁶

BRD3

BRD4

N/A

Osteoarthritis

Human chondrosarcoma cells (SW1353)

IL1B, TNF

H4K5Ac, H4K8Ac, H4K12Ac

MMP1, MMP3, MMP13, ADAMTS4

I-BET151

¹¹⁸

BRD2 BRD3 BRD4

N/A

Failure of bone healing

C2C12 and MC3T3-E1 cell lines, BMDMs

TNF

RUNX2, SP7

N/A

ALP, RUNX2, SP7

N-methylpyrrolidone and N, N-dimethylacetamide, JQ1

¹⁹⁷

BRD4

Upregulation

Articular cartilage of osteoarthritis

Human chondrocyte cell line sw1353 cells

IL1B

RELA

H3K27Ac

HMGB1, IL1B

JQ1

¹⁷⁶

BRD2

BRD3

BRD4

Upregulation

Rheumatoid arthritis

Human rheumatoid arthritis fibroblast-like synoviocytes

TNF, IL1B

JUN, RELA

N/A

TNF, IL1B, IL6, IL8, IL17, IL18, MMP1, MMP3, MMP13

JQ1, I-BET151

^51,98,177

BRD2 BRD3 BRD4

Upregulation

Spontaneous preterm birth

Myometrial cells, amnion epithelial and mesenchymal cells

LPS, IL1B

RELA

N/A

IL6, CCL2, CXCL1, CXCL8

JQ1

³¹

BRD4

Upregulation

Preeclampsia

Primary trophoblasts, human umbilical vein vessel endothelial cells

TNF

N/A

N/A

IL6, CXCL8, CCL2, CXCL1, FLT1

N/A

³²

BRD4

N/A

Autoimmune uveitis (EAU)

Human CD4 + T cells, human Th17-polarized cells

Anti-CD3/CD28

RORC

N/A

IL17A, IL22, RORC, IL10

GSK151, JQ1

¹⁷⁸

BRD2

Upregulation

Inherited retinal degeneration

Mouse primary microglias

LPS

N/A

N/A

TNF, CCL2, IL1B, IL6, RANTES

JQ1, RVX-208

⁴⁵

BRD2 BRD3 BRD4

N/A

Age-related macular degeneration

Human retinal pigment epithelial cell line (ARPE-19)

Etoposide

RELA

N/A

IL6, IL8

JQ1, PFI-1, I-BET151

¹⁷⁹

BRD2

N/A

Psoriasis

Primary human keratinocytes, HS27 dermal fibroblasts

IL17A, TNF, IL22

RELA

IL8, CXCL1, CXCL2, CXCL6, CXCL8, GCSF, CCL20

JQ1, I-BET151

¹⁹⁸

BRD2 BRD3 BRD4

N/A

Psoriasis-like inflammation

N/A

Imiquimod

RORC

N/A

IL17A, IL22

JQ1

¹⁸⁰

BRD4

N/A

Periodontitis

RAW264.7 cells

LPS

RELA

N/A

IL1B, IL6, TNF, TLR2, TLR4

JQ1

⁵¹