Increased expression of the interleukin-1 receptor-associated kinase (IRAK)-1 is associated with adipose tissue inflammatory state in obesity

Abstract

BackgroundThe emerging role of TLR2/4 as immuno-metabolic receptors points to key involvement of TLR/IL-1R/MyD88 pathway in obesity/type-2 diabetes (T2D). IL1R-associated kinase (IRAK)-1 is a critical adapter protein (serine/threonine kinase) of this signaling pathway. The changes in adipose tissue expression of IRAK-1 in obesity/T2D remain unclear. We determined modulations in IRAK-1 gene/protein expression in the subcutaneous adipose tissues from lean, overweight and obese individuals with or without T2D.MethodsA total of 49 non-diabetic (22 obese, 19 overweight and 8 lean) and 42 T2D (31 obese, 9 overweight and 2 lean) adipose tissue samples were obtained by abdominal subcutaneous fat pad biopsy and IRAK-1 expression was determined using real-time RT-PCR, immunohistochemistry, and confocal microscopy. IRAK-1 mRNA expression was compared with adipose tissue proinflammatory mediators (TNF-α, IL-6, IL-18), macrophage markers (CD68, CD11c, CD163), and plasma markers (CCL-5, C-reactive protein, adiponectin, and triglycerides). The data were analyzed using t test, Pearson’s correlation, and multiple stepwise linear regression test.ResultsIn non-diabetics, IRAK-1 gene expression was elevated in obese (P = 0.01) and overweight (P = 0.04) as compared with lean individuals and this increase correlated with body mass index (r = 0.45; P = 0.001) and fat percentage (r = 0.36; P = 0.01). In diabetics, IRAK-1 mRNA expression was also higher in obese as compared with lean subjects (P = 0.012). As also shown by immunohistochemistry/confocal microscopy in non-diabetics and by immunohistochemistry in diabetics, IRAK-1 protein expression was higher in obese than overweight and lean adipose tissues. IRAK-1 gene expression correlated positively/significantly with mRNAs of TNF-α (r = 0.46; P = 0.0008), IL-6 (r = 0.30; P = 0.03) and IL-18 (r = 0.31; P = 0.028) in non-diabetics; and only with TNF-α (r = 0.32; P = 0.03) in diabetics. IRAK-1 expression also correlated positively/significantly with CD68 (r = 0.32; P = 0.02), CD11c (r = 0.30; P = 0.03), and CD163 (r = 0.43; P = 0.001) in non-diabetics; and only with CD163 (r = 0.34; P = 0.02) in diabetics. IRAK-1 mRNA levels also correlated with plasma markers including CCL-5 (r = 0.39; P = 0.02), C-reactive protein (r = 0.48; P = 0.005), adiponectin (r = −0.36; P = 0.04), and triglycerides (r = 0.40; P = 0.02) in non-diabetics; and only with triglycerides (r = −0.36; P = 0.04) in diabetics. IRAK-1 expression related with TLR2 (r = 0.39; P = 0.007) and MyD88 (r = 0.36; P = 0.01) in non-diabetics; and MyD88 (r = 0.52; P = 0.0003) in diabetics.ConclusionsThe elevated IRAK-1 expression in obese adipose tissue showed consensus with local/circulatory inflammatory signatures and represented as a tissue marker for metabolic inflammation. The data have clinical significance as interventions causing IRAK-1 suppression may alleviate meta-inflammation in obesity/T2D.Electronic supplementary materialThe online version of this article (doi:10.1186/s13098-015-0067-7) contains supplementary material, wh...

Deficiency in IRAK4 activity attenuates manifestations of murine Lupus

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“…1C), indicating that enhanced TLR‐induced activation of MAPK is lupus‐specific. Since IRAK kinases regulate inflammatory responses , we determined IRAK4 and IRAK1 levels in splenic macrophages derived from 16 weeks‐old BXSB/ Yaa or BXSB mice. Figure shows comparable levels of IRAK4 or IRAK1 (C, D) mRNA and proteins (B) in splenic macrophages from lupus‐prone or control mice treated with medium, LPS or Lxrb.…”

Adipose tissue expression of CCL19 chemokine is positively associated with insulin resistance

“…After removal, the biopsy tissue was further incised into smaller pieces, rinsed in cold phosphate buffered saline, fixed in 4% paraformaldehyde for 24 hours, and then embedded in paraffin for further use. At the same time, freshly collected adipose tissue samples (~50‐100 mg) were preserved in RNAlater and stored at −80°C until use …”

“…At the same time, freshly collected adipose tissue samples (~50-100 mg) were preserved in RNAlater and stored at −80°C until use. 16 Figure 1A and B). Furthermore, elevated CCL19 gene expression correlated positively with BMI (r = 0.253, P = 0.049) ( Figure 1C).…”

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