We found that in a sample of adults who grew up in low SES homes, maternal warmth during childhood was associated with reduced pro-inflammatory signaling. As adults, those who experienced high maternal warmth showed reduced immune cell responsivity to challenge (as indicated by less PBMC stimulated production of IL-6), and at the functional genomic level, reduced bioinformatic indications of activity by pro-inflammatory (NF-κB) and immune-activating (AP-1) transcription factors compared to their low warmth counterparts. These findings are significant because they suggest the possibility that the excess inflammatory activity linked to low SES may be mitigated, in part, by the presence of a warm and supportive family climate early in life.
These results are consistent with the notion that adverse social environments engender heightened signaling of pro-inflammatory transcription control pathways in childhood and adulthood 19–23
as well as heightened systemic inflammation in adulthood 52, 53
, and that maternal warmth experienced during childhood may serve to reduce these states. Our results add to recent theoretical discussions about how positive psychological and support factors may be able to biologically protect those who experience adversity from poor health outcomes 35, 54, 55
, and complement research that has shown protective effects of biological traits such as genetic polymorphisms under certain adverse conditions 56, 57
. Furthermore, given the causal role that inflammatory cytokines are hypothesized to play in major depression 29, 30
, the reduced inflammatory signaling seen among high maternal warmth individuals suggests the possibility that supportive family environments early in life could potentially be protective against later depression in part because of their effects on inflammatory pathways.
Previous human research on the biological profiles associated with positive psychosocial factors experienced under adversity has largely focused on neuroendocrine or cardiovascular risk outcomes. For example, a program to teach parenting skills to foster parents produced greater declines in cortisol among maltreated children in comparison to children in foster care whose parents did not receive the program 58
. Similarly, maltreated children who have high ego resilience, as well as psychologically healthy adult survivors of child abuse, show different profiles of cortisol and functioning of the hypothalamic pituitary adrenal axis compared to those without resilience characteristics 59, 60
. Positive relationships with others also have been linked to less detrimental neuroendocrine and cardiovascular outcomes. For example, effects of current cumulative adversity on allostatic load (a composite of cardiovascular and neuroendocrine measures) did not occur in children who experienced high maternal warmth 36
. Adults who experience positive relationships currently did not show detrimental effects of low maternal warmth on adult allostatic load 37
. Additionally, high quality family or social relationships mitigated the relationship between low SES or parental loss and cardiovascular risk (e.g., blood pressure, cholesterol profiles) in adults 61–62
. Finally, the relationship between current SES and glycosylated hemoglobin in adults has been found to be stronger among those currently low in psychological well-being 38
. The present study is unique both in focusing on early life factors and their links with adult biology, as well as in demonstrating a biological signature associated with maternal warmth that spans from systemic inflammatory markers down to indicators of functional genomic activity.
In addition to our hypotheses relating to NF-κB and AP-1, exploratory analyses also revealed downregulation of the OCT, ELK, and GATA family of transcription factors, as well as upregulation of CREB. Interestingly, these same pathways have emerged in several other studies of the transcription control pathways linked to social adversity 19, 22, 23, 63
. CREB is activated by a variety of different physiologic receptor systems, some of which would not be consistent with the other patterns seen in this study. However, one CREB modulator that may be relevant to the present findings is the neurotrophin Brain-Derived Neurotrophic Factor (BDNF, which in addition to being found in the brain, can also be produced by immune cells 64
). Low levels of BDNF have been implicated in depression, and conversely, antidepressant treatments (both pharmacologic and psychotherapeutic) have been found to increase BDNF 65, 66
. Moreover, increases in BDNF are linked to activation of CREB, and increases in CREB phosphorylation are also seen with antidepressant treatment 67, 68
. This suggests the possibility that the upregulation of CREB seen in the present study could have implications for protection against depression. In addition, activated CREB can inhibit NF-κB-mediated transcription by competing for transcriptional co-factors such as p300/CBP 69
. Activated CREB may reflect increased upstream activity of PKA, which can also inhibit NF-κB 70
. Given the inhibitory effects of PKA/CREB on NF-κB, the CREB activation observed in this study may be one plausible mechanism for reciprocal reductions in NF-κB-mediated gene expression.
In the present study, we did not find evidence that impaired glucocorticoid signaling played a role in the differential pro-inflammatory activity of low-versus high-maternal warmth subjects (there were no significant differences in the expression of genes with response elements for the glucocorticoid receptor, GR). This is intruiging because previous studies have suggested that the effects of adverse social environments on pro-inflammatory signaling pathways may operate in part via increased glucocorticoid resistance 19, 20, 22
. Patterns for CREB were also different, and taken together, these findings suggest that while adverse social environments and protective support factors both appear to have effects at the genomic level, each has its own specific mediational fingerprint. That is, low SES appears to increase pro-inflammatory transcription control pathways via increased glucocorticoid resistance, whereas maternal warmth appears to reduce pro-inflammatory transcription signaling via other pathways that do not involve the GR.
The present analyses focus on cis-regulatory activity, and thus cannot definitively rule out the possibility that altered GR signaling might contribute to the observed NF-κB inhibition through non-transcriptional mechanisms (e.g., protein-protein interactions) 71
. However, GR transcriptional regulation and protein-protein interactions tend to correlate because they are both induced by glucocorticoid ligation of the GR 71
. In the absence of any detectable change in GR-mediated transcription, the most parsimonious interpretation of the data is that GR signaling alterations are not driving the observed inhibition of NF-κB.
Despite differences in immune cell responsivity to challenge and bioinformatic indications of pro-inflammatory signaling, we found no statistically significant differences by maternal warmth in CRP levels, although group means were in the hypothesized direction. Because this was a healthy and relatively young sample, this could mean that differences at the level of systemic inflammation take time to emerge. Alternatively, it could be that larger samples are required to detect differences at this level.
Controlling for a variety of demographic and behavioral factors did not substantially affect study results. This indicates that the differences between low and high maternal warmth participants cannot be attributed to differences in gender, age, ethnicity, or various health behaviors. In addition, because the low and high maternal warmth groups did not differ on current SES, the results observed in this study do not appear to be due to effects of current socioeconomic environments on inflamatory signaling pathways.
Strengths of the present study include the empirical testing of theoretical models of biology profiles associated with maternal warmth using a well-defined molecular mechanism for disease risk. A second strength lies in the in-depth assessment of pro-inflammatory profiles ranging from indicators of systemic inflammation to genome-wide microarray analyses of gene expression. A third strength lies in the confirmation of early life SES status from parents, rather than from the study participants themselves. Limitations include the small sample size (although it is similar to other microarray studies of social adversity 19, 21, 23
), the retrospective nature of assessments of parental warmth and early life SES, and the inability to infer causality based on the study design. Future studies should follow clinical outcomes over time to characterize the implications of these immune and gene expression profiles for psychiatric illnesses, and as well to determine the degree to which maternal warmth early in childhood protects low SES individuals, much as higher SES status does. In addition, the potential benefits of paternal, in addition to maternal, warmth would be important to establish. Finally, it would be important to identify the underlying biological mechanisms by which early life factors contribute to persistent effects on inflammatory signaling by exploring the role of processes such as epigenetics 72
In sum, the present study found that high maternal warmth among those low in SES early in life was associated with reduced PBMC response to TLR stimulation, and at the genomic level, reduced bioinformatic indications of pro-inflammatory transcription factor activity. Given that pro-inflammatory states have been strongly implicated in both mental health disorders such as depression29
, as well as in physical illnesses such as cardiovascular disease 26
, this suggests that individuals who grow up low in SES but who have warm maternal figures may be less likely to develop a number of mental and physical illnesses later in life. If true, these findings could have important public policy and public health implications. Working to alleviate poverty, as lofty and important a goal as this is, has remained an intractable problem in our society. Complementing this effort, encouraging and teaching parenting behaviors that facilitate warm emotional climates, even in the face of adversity, might prove to be a supporting, effective target of intervention (as suggested by cross-fostering and environmental manipulation studies in previous animal research 40, 73
). To the extent that promoting such environments early in children’s lives can be shown to have causal protective effects, we may one day be able to partially ameliorate the inflammatory and subsequent health effects of low early life SES environments through increasing the warmth and supportiveness of family relationships in at-risk children.